- Open Access
Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation
© Resende and Adhikari; licensee BioMed Central Ltd. 2009
Received: 8 June 2009
Accepted: 27 August 2009
Published: 27 August 2009
Acetylcholine (ACh) has been shown to modulate neuronal differentiation during early development. Both muscarinic and nicotinic acetylcholine receptors (AChRs) regulate a wide variety of physiological responses, including apoptosis, cellular proliferation and neuronal differentiation. However, the intracellular mechanisms underlying these effects of AChR signaling are not fully understood. It is known that activation of AChRs increase cellular proliferation and neurogenesis and that regulation of intracellular calcium through AChRs may underlie the many functions of ACh. Intriguingly, activation of diverse signaling molecules such as Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C and c-Src is modulated by AChRs. Here we discuss the roles of ACh in neuronal differentiation, cell proliferation and apoptosis. We also discuss the pathways involved in these processes, as well as the effects of novel endogenous AChRs agonists and strategies to enhance neuronal-differentiation of stem and neural progenitor cells. Further understanding of the intracellular mechanisms underlying AChR signaling may provide insights for novel therapeutic strategies, as abnormal AChR activity is present in many diseases.
Acetylcholine (ACh) is an ancient signaling molecule,  and is present in both prokaryotes and eukaryotes [2–4]. Although ACh has been extensively studied for its role as a neurotransmitter, it also has autocrine functions  in diverse cell types. ACh has been shown to promote cytoskeleton organization, cellular proliferation, differentiation and apoptosis [2–4, 6–8] throughout development [2, 3, 9]. Intriguingly nAChR signaling pathways have been preserved throughout evolution , suggesting that they have critical functions. We shall attempt to discuss the physiology of ACh as well as ACh's relevant downstream pathways in apoptosis, cell proliferation and neuronal differentiation of embryonic stem cells.
Interestingly, nicotinic receptors are expressed in undifferentiated and differentiating cells, [8, 11–13] suggesting that ACh-mediated signaling between neuronal and non-neuronal cells may influence cell fate [8, 11, 12, 14]. Supporting this idea, ACh has been shown to modulate neuronal cell differentiation during development [15, 16]. Moreover, transfecting a non-neuronal cell line such as a neuroblastoma with choline acetyltransferase induces expression of neuronal markers, muscarinic receptors and production of ACh . Lastly, ACh also regulates cell proliferation  and apoptosis . These and other findings marked the beginning of a new field: the role of nAChRs in the development and progression of cancer and in stem cell physiology.
Nicotinic ACh receptors
ACh receptors can be nicotinic (nAChRs), which are ion channels, or G protein-coupled (GPCR) muscarinic receptors (mAChRs). In the central nervous system, nAChRs have been shown to regulate diverse processes such as neurotransmitter release and cellular excitability. Nicotinic receptors also influence physiologic processes such as arousal, sleep, fatigue, anxiety, pain processing, hunger and various higher cognitive functions. [19–22].
nAChRs structure and function
nAChRs are multisubunit proteins of neuromuscular and neuronal origins. These receptors form ligand-gated ion channels that mediate synaptic transmission both in the neuromuscular junction and between neurons. Since various neuronal nAChR subunits exist, nAChRs can be formed by different combinations of subunits. . Nicotinic receptors of different compositions exhibit different specificities for various ligands and are thereby pharmacologically distinguishable. For example, the elapid alpha-neurotoxins that block activation of nAChRs at the neuromuscular junction do not block activation of other neuronal nAChR subtypes .
A functional nAChR consists of five subunits which may be different (certain combinations of α1–9 and β1–4, γ, δ, ε subunits) or identical (α7–9) i.e. subunits . All subunits have a similar structure with one extended extracellular domain (N-terminal), four transmembrane domains (M1–M4), one intracellular domain of variable length which joins M3 and M4 domains and one small extracellular C-terminal domain . The binding site for ACh and other agonists is located on the N-terminal extracellular domain at the boundary between α and non-α subunits. In heteromeric neuronal receptors the α and β subunits contribute to the binding site The amino acid sequence analysis of various subunits shows that nicotinic receptors can be divided into three sub-classes. The first family includes α-bungarotoxin-sensitive muscle-type heteromeric receptors, typically found in skeletal muscle and fish electrical organs, with (α1)2β1γδ and (α1)2β1γε pentameric structures in fetal and adult form, respectively. The second family includes nAChRs consisting of α-bungarotoxin-insensitive, heteromeric subunits. These receptors have various combinations of α2, α3, α4 and α6 with β2, β4, α5 and β3 subunits. The third family includes α-bungarotoxin-binding nicotinic neuronal receptors consisting of five identical subunits (α7, α8 or α9) .
Neuronal nAChRs are expressed in the autonomic nervous system ganglia, and in the CNS, in post- pre and extra synaptic locations. The α7 nAChR subtype is highly expressed in regions of the brain involved in learning and memory, such as the hippocampus and the neocortex . This subtype has a particularly high permeability for calcium ions, increases glutamatergic neurotransmission, and modulates neuronal plasticity by influencing the growth of axons .
Studies on the structure, functions and pharmacology of nAChRs neuronal receptors are necessary because these receptors are involved in a large number of nervous system diseases (for review see Clementi and Adlkofer Special Issue on "nicotinic neuronal receptors" 2000).
Muscarinic ACh receptors
mAChRs structure and function
Muscarinic receptors are members of the G Protein-coupled receptors (GPCRs), and are composed of a family of five receptor subtypes (M1, M2, M3, M4 and M5). These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The distribution of these receptor subtypes in the brain and other organs has been extensively studied. M1 is the predominant subtype found in the cerebral cortex and is involved in the control of cognitive functions. M2 is the main subtype in the heart and is believed to play a role in the control of heart rate. M3 is involved in gastrointestinal and urinary tract functioning as well as sweating. M4 is present in the brain and may have a role in locomotion. Lastly, M5, also present in the brain, modulates certain functions of the central nervous system associated with the dopaminergic system, such as dopamine release in the nucleus accumbens following mesopontine stimulation in mice . The M5 subtype is also important for brain-stimulation reward , opiate reward , latent inhibition learning and amphetamine-induced locomotion [32–34].
As mAChRs are involved in such a wide array of processes, it is not surprising that muscarinic signaling has been shown to be abnormal in many diseases, such as overactive bladder [35, 36], chronic obstructive pulmonary disease [36, 37], neurodegenerative disease as Alzheimer's disease , dementia , Sjogren's disease , vascular dementia  and others. Consequently, there is considerable interest in finding pharmacological agents to selectively modulate each receptor subtype. Agonists such as muscarine and pilocarpine and antagonists such as atropine have been known for over a century; however, these drugs do not target specific subtypes. Unfortunately, little progress has been made in the discovery of subtype-selective compounds making it challenging to study specific functions of individual receptor subtypes. The clinical utility of classic muscarinic antagonists such as atropine is limited due to the high incidence of both peripheral and central adverse effects such as tachycardia, blurred vision, dryness of mouth, constipation, dementia, etc. Atropine derivatives such as ipratropium bromide are better tolerated but most of them lack of selectivity for specific muscarinic receptor subtypes. [42–44]. Thus, the search for subtype selective muscarinic drugs remains an active area of research.
Muscarinic subtypes are coupled to different GPCRs, leading to activation of distinct downstream pathways. M1, M3 e M5 are G-protein coupled receptors (subunit α of the Gq/11 family), while M2 and M4 subtypes are coupled to the α subunit of Gi and Go. Consequently different second messenger dependent-pathways being activated by each muscarinic subtype. For example, phospholipase Cβ (PLC) is activated by M1, M3 and M5, while adenilate cyclase is activated by M2 and M4 subtypes . Processes modulated by pathways involving these G-proteins include smooth muscle contraction (through M2 and M3 receptors), stimulation of glandular secretion (M3 receptors) and inhibition of cardiac voltage-dependent calcium channels (M2 subtypes) .
Expression and function of n- and mAChRs in embryonic cells
ACh  is present in the brain prior to axonogenesis and synaptogenesis, suggesting that it may mediate non-classical signaling. Furthermore, muscarinic receptors are widely expressed in embryonic cells [8, 13, 47–54], and have been shown to regulate neuronal cell proliferation and differentiation [47, 50, 51]. In neuronal progenitor cells, muscarinic receptor expression also occurs prior to the onset of synaptogenesis and neurotransmission [9, 55], indicating that ACh may act via a local autocrine loop in the embryo. In early development, M2 receptors are expressed in the dorsal root ganglia neurons, as well as in non-neural cells such as Schwann cells, where they control sensory neuronal differentiation and axonal growth . Intriguingly, muscarinic receptors are also expressed in primary and metastatic tumor cells in which ACh also acts in an autocrine fashion . As discussed above, expression of muscarinic receptors is an embryonic trait. The expression of these receptors in tumor cells [8, 13, 58–63] likely arises from reactivation of embryonic genes during malignant growth . Proliferation due to mAChR activation has been reported in many tumor cells. For example, activation of muscarinic M1, M3 or M5 muscarinic receptors (but not M2 or M4 receptors) induces foci of transformation in 3T3 cells [64, 65]. Furthermore, activation of the Gqα11-coupled muscarinic receptors in various cell lines [59, 66, 67] or the α7 nicotinic subtype in P19 embryonic carcinoma cells [13, 68, 69] induces growth and proliferation. These effects of muscarinic receptor activation depend on the cellular phenotype [70, 71]. Activation of M3 induces proliferation in human colon cancer cell lines and prostate carcinoma cells . In contrast, activation of endogenous M3 inhibits DNA synthesis in several small cell lung carcinoma cell lines . These contradictory responses also occur in cells transfected with mAChRs, as transfected M3 mAChRs has been reported to both inhibit and stimulate proliferation [73–75]. In cells deprived of trophic factors, muscarinic M3 receptor activation elicits anti-proliferative signals via activation of the small GTP-binding protein, Rac1 [72, 76, 77]. However, muscarinic agonists can also inhibit apoptosis. Pretreatment of tumor cell lines with muscarinic agonists inhibits apoptosis induced by DNA damage [78–81]. Moreover, agonists for M1, M3 and M5 subtypes showed a protective response against apoptosis in Chinese hamster ovary cells transfected with these muscarinic receptors . This effect occurs via a mechanism independent of Ca2+/PLC signaling that may involve upregulation of the anti-apoptopic protein Bcl-2 [6, 83]. It is unclear whether muscarinic receptor activation is related to tumor growth and stem cell proliferation [8, 84–87]. In addition to morphogenesis, non-neuronal muscarinic receptors also control cell migration, as M3, M4 and M5 subtypes were shown to control cell migration by facilitating fibronectin-induced movement [58, 88–90]. Contraction and aggregation of cells in embryonic tissue is also induced by muscarinic receptor activation . In this way, mAChRs could modulate cellular movement during morphogenesis [92, 93].
Apoptotic signaling pathways
Apoptotic pathways associated with mAChRs
By targeting two signaling pathways, the MAPK/ERK pathway [107, 108] and the PI3-kinase signaling pathway , it would be possible to gain new insights on the intracellular signaling pathways through which mAChRs inhibit apoptosis. It has been suggested that these pathways inhibit caspases [77, 79, 102]. To this end, it was shown that PKB/Akt, the downstream target of PI3-kinase, can inhibit both caspase-9, [110–112] and the pro-apoptotic protein Bad [112–115]. However, PKB/Akt can also be activated by other pathways. These are mediated by protein kinase A (PKA), calcium/calmodulin-dependent kinase and Bad [114, 116–119]. Interestingly, inhibitors of the PI3-kinase or MAPK/ERK pathways could not suppress the muscarinic effect on caspases, although all were able to inhibit the muscarinic-dependent phosphorylation of PKB/Akt and MAPK/ERK. Furthermore, previous studies in PC12 cells have shown that these inhibitors block survival effects and ERK and PI3-kinase signaling [120, 121]. It has been suggested that the MAPK/ERK and PI3-kinase pathways are not essential for mediating the muscarinic effect on caspase activity in PC12 cells , but rather that this effect is mediated by an unidentified pathway. This finding is in line with recent studies showing that in some cases the survival effects of growth factors and cytokine receptors are mediated by pathways independent of both MAPK/ERK and PI3-kinase. For example, neither the survival effect of nerve growth factor (NGF) on sympathetic neurons  or rat-1/MycER cells transfected with TrkA , nor that of granulocyte/macrophage colony-stimulating factor on MC cells, is mediated by the PI3-kinase pathway . Moreover, the MAPK/ERK and the PI3-kinase pathways are not essential for the survival effect of NGF on apoptosis induced by ceramide in PC12 cells . However, the PI3-K/Akt pathway has an established role in NGF-promoted cell survival . Activation of PI3-K by NGF initiates a cascade involving Akt, which leads to the phosphorylation and inhibition of the pro-apoptotic protein Bad and activation of the pro-survival inhibitor κB kinase α (IKKα) [116, 126]. Blockade of the PI3-K/Akt pathway by a dominant negative Akt mutant or treatment of cells with PI3-K inhibitors reveal that activation of this signaling pathway is required for NGF-promoted cell survival . However, it was shown that pertussis toxin did not inhibit Akt phosphorylation. This finding is consistent with the previous observation of pertussis toxin having a more profound inhibitory effect during the early phase of NGF-induced Erk1/2 activation . Upon activation, the TrkA receptor activates the PI3-K pathway, leading to activation of Akt in sympathetic neurons . Previous studies have shown that TrkA forms complexes with GRK2 and GAIP/GIPC (GAIP-interacting protein, C terminus) [128, 129], thereby providing a bridge to link TrkA and G protein signaling pathways. Furthermore, there is prior evidence pointing to a functional association between pertussis toxin-sensitive G proteins and growth factor receptors such as the insulin receptor tyrosine kinase . In addition, some pertussis toxin-sensitive growth factor-induced responses have been reported. For example, insulin-like growth factor 1 has been shown to activate Gi and release Gβγ subunits [131, 132], while TrkA is able to utilize Gi/o to stimulate Erk1/2 [128, 133]. Increasing evidence shows that GPCRs often cooperate with RTKs (receptor tyrosine kinases) in the regulation of numerous signal transduction pathways [134–136]. More recently, a report has demonstrated that NGF and lysophosphatidate receptor signaling systems can interact to promote G protein-mediated activation of the Erk pathway . These observations are consistent with the notion that TrkA can utilize pertussis toxin-sensitive Gi/o proteins to activate Akt, thereby inhibiting Bad and stimulating the NFκB regulator, IKK, via Gαγ activation [137, 138] to allow cell survival through the M3 subtype [83, 139, 140].
One candidate for mediating the muscarinic effect on caspases is sphingosine-1-phosphate, which was shown to play an important role in the survival effect of NGF on PC12 cells . Interestingly, sphingosine-1-phosphate can be induced by the M2 muscarinic receptor . Intriguingly, inhibition of the PI3-kinase pathway partially attenuates the muscarinic survival effect on the viability of the cells but not on caspase inhibition. One possible explanation is that serum-deprived cells can die via both caspase-dependent and -independent pathways, as shown in some apoptotic paradigms such as Bax-induced cell death in the presence of caspase inhibitors [143–145]. Despite the fact that the caspase-dependent pathway seems to play a major role in the death of serum-deprived PC12 cells, it is possible that once this pathway is inhibited, the caspase-independent pathway has a major role. However, one cannot exclude the possibility that there are unknown caspases which are activated and involved in apoptosis induced by trophic-factor-deprivation and that these caspases are inhibited by the muscarinic receptor in a different mechanism than that used to inhibit the DEVDase caspases and caspase-2. It was shown that NGF withdrawal from differentiated PC12 cells induces expression of FasL, which in turn may contribute to the apoptotic process via activation of the CD95 receptor [146, 147]. In this case, it is still possible that muscarinic receptors will inhibit the activation of caspase-8, the caspase which is directly activated when CD95 is activated [80, 115, 148] by a PI3-kinase-dependent mechanism as was shown for CD3 activation in Fas-treated Th2-type cells [80, 115]. In some systems, one signaling pathway appears to be sufficient for mediating survival induced by trophic agents such as NGF (PI3-kinase) and N-acetylcysteine (ERK) [109, 120]. However, in other systems, the survival effect may require the combined action of several signaling pathways. For example, insulin-like growth factor-1 inhibited apoptosis in differentiated PC12 cells requires both PI3-kinase and MAPK/ERK signaling pathways [127, 149, 150]. It has been suggested that the muscarinic survival effect could be mediated by the combined effect of at least two different pathways. One pathway may lead to caspase inhibition and be independent of PI3-kinase and ERK signaling. This pathway could be mediated by the Gi/o-coupled receptors. The other pathway would act through Gq and may involve the PI3-kinase pathway, and could promote survival by a mechanism that does not affect caspases and that could be mediated by the Gq-coupled receptors.
Previous reports showed that muscarinic receptor stimulation leads to activation of the Rho family of small G-proteins [151, 152]. This pathway can lead to activation of Rho kinase  and is critical for the protective capacity of muscarinic receptors. It has been demonstrated that excitatory receptor agonist-induced Rho activation is Ca2+-dependent . The ability of mAChRs to activate SRF-mediated gene transcription and the involvement of G protein subunits in SRF activation were investigated in Jurkat T cells. It has been shown that Gαq-coupled M1, but not Gαi/o-coupled M2 receptors can activate SRF through a RhoA-mediated pathway [73, 155]. In contrast, M3 mAChR failed to activate SRF even though M1 and M3 are thought to induce similar signaling pathways that involve Gαq/11. Yet, Gαq coupling of both M1 and M3 remained intact, as revealed by a robust calcium response in Jurkat T cells. Moreover, use of the chimeric Gα protein construct Gαiq5, which allowed the M2 receptor to signal along Gαq/11-mediated pathways, restored the Ca2+ response for M2, but not SRF activation. This suggests either that the activation of SRF through M1 involves a Gαq/11-independent pathway or that Gαq/11 is insufficient in Jurkat T cells. The inhibition of M1-SRF signaling by co-transfection with the Gαq/11 suppressors, RGS2 and RGS4, indicated that Gαq/11 did play a role in M1-SRF activation, but it appeared to be insufficient per se. However, an increase of M1-SRF signaling inhibition was observed when intracellular calcium was decreased.
Apoptotic pathways associated with nAChRs
Nicotine can also promote anti-apoptotic effects through activation of PKC, PKA and NF-κB, and downregulation of the tumor suppressor p53 [160, 161]. Nicotine-induced NF-κB phosphorylation promotes the phosphorylation of the apoptotic protein Bad (Bcl-2 antagonist of cell death), which becomes inactivated and prevents cell death. Other pathways underlying the anti-apoptotic effects of nicotine include the MEK and PI3K pathways . It was previously shown that ERKs, AKT, and PKA could function as a Bad Ser112, Ser136, or Ser155 kinase, respectively [164–167]. One interesting study demonstrated that nicotine-induced Bad phosphorylation is mediated by β-adrenergic receptors  (for a review see ), and that nicotine can also induce phosphorylation of Bax (another Bcl-2 antagonist of cell death) through PKCζ, thereby inactivating Bax and suppressing cell death [169, 170].
The protective effects of nicotine have been studied in NSCLC and PC12 cell lines, as well as in other experimental systems [171–176]. Nicotine can protect A549 NSCLC cells against apoptosis induced by anticancer drugs through the upregulation of XIAP and survivin in a α3-nAChR-dependent manner . Furthermore, administration of nicotine in the CNS can stimulate release of neurotransmitters [177, 178] and neurotrophic factors, such as basic fibroblast growth factor (bFGF or FGF-2) and brain-derived neurotrophic factor (BDNF). In addition, nicotine exposure can lead to elevated cellular cAMP levels . It was demonstrated that nicotine attenuates both arachidonic acid-induced caspase activation and apoptosis of spinal cord neurons . However, controversy exists on the specific nAChR subunit responsible for the anti-apoptotic effects of nicotine. The α7 and the α4β2 subtypes may play the most significant role in the central nervous system [180, 182, 183]. Data from some laboratories indicate that phosphorylation of ERK1/2 in nicotine-treated neurons can be specifically prevented by pre-exposure to the α7 blocker α-bugarotoxin, but not dihydro-β-erythroidine (an antagonist of the β2 subunit) [172, 178, 181], indicating an important role for the α7 receptor in nicotine-mediated neuroprotection. On the other hand, studies in tumor and tumoral stem cells have implicated the dihydro-β-erythroidine-sensitive α3 and α4 receptors. This finding implies that the proliferative effects (mediated by α7 nAChR) and pro-survival effects (mediated by α3 or α4 nAChR) of nicotine are mediated by two distinct classes of receptors [8, 13, 162, 171]. These data demonstrate that during differentiation there are changes in nAChR activity and function. This could be due to β-adrenergic receptor activation through α7 nAChR, which has been found to mediate the anti-apoptotic effects of nicotine in some cell lines [184–186] (for a more detailed discussion see ). Such discrepancies can be partially explained by the pleiotropic nature of nAChR subunit inhibitors. It is also possible that the anti-apoptotic effects of nicotine are mediated by different nAChR subunits in a tissue-specific manner. These possibilities underscore the need for further studies to identify the nAChR subunits responsible for the anti-apoptotic effects of nicotine.
It is known that ERK1/2 signaling can participate in the neuroprotective effects of nicotine through a variety of different mechanisms. Previous reports showed that ERK2 can increase expression of bcl-2 and inhibit apoptosis . In addition, the neuroprotective effects of ERK1 and ERK2 may be related to activation of a variety of transcription factors, which in turn can regulate transcription of neurotrophic factors, leading to overexpression of "survival" genes and enhanced neuronal viability. Among the transcription factors that are involved in the ERK-mediated cellular survival are Elk1, nuclear factor-κB (NF-κB), and cAMP response element (CRE)-binding factor (CREB) [188–190]. A role for NF-κB in neuronal survival has been suggested . In addition, recent evidence indicates that CREB has a crucial role in regulation of cell viability , as it is required to induce transcription of BDNF . Elk1 functions as a nuclear transcriptional activator through the interaction with the serum response element (SRE), which is present in the promoter of many immediate early genes . Among others, Elk1 is involved in regulation of expression of FGF-2 [195, 196].
Signaling pathways of mAChRs involved in proliferation and neuronal differentiation
Activation of M2 and M3 receptors has been shown to increase proliferation of tumoral cells in a dose-dependent manner. Cellular proliferation induced by the M3 subtype is mediated by production of inositol triphosphate, [8, 66] and nitric oxide [for a review see ], while the effects of the M2 subtype were dependent on concomitant activation of M1, promoting the release of E2 prostaglandin and arginase catabolism. These events are related to tumoral cell growth , and inhibition of caspases [79, 83].
In murine mammary adenocarcionoma cells, the M3 subtype is the most highly expressed muscarinic receptor. Stimulation of M3 receptors activates adenilate cyclase, phospholipase A2 (PLA2), IP3 and diacylglicerol (DAG) through PLC . Each of these molecules in turn activates different pathways. DAG activates protein kinase C (PKC), while IP3 induces release of calcium from intracellular stores. It is known that both pathways regulate MAPK and ERK signaling. Free intracellular Ca2+ can modulate MAPK/ERK either through Ca2+-dependent protein tyrosine kinase (PYK2)  or by Ca2+/calmodulin kinase (Ca2+/CaM) . PKC isoforms are also known to regulate MAPK/ERK through Raf-1  or through transactivation of the epidermal growth factor receptor (EGFR) mediated by the Src/PYK2 complex (Figures 2 and 3) .
Recent evidence suggests that activation of MAPK/ERK through GPCRs occurs through PKC-dependent and -independent mechanisms, depending on the receptor activated and on the cell type [206, 207]. It is known that activation of MAPK/ERK GPCR agonists mediate cell proliferation [55, 208], and that pathways involving cholinergic receptors seem to depend on the cell growth [8, 74].
Stimulation of mAChRs promotes an increase in [Ca2+]i and induces phosphorylation of MAPK/ERK in MCF-7 human breast cancer cells . Activation of this pathway increases protein synthesis and cell proliferation through MAPK kinase, besides inducing DNA synthesis in neuronal progenitor cells during early neurogenesis . Inhibition of PLC or incubation of cells in a calcium free medium did not alter MAPK/ERK phosphorylation; however, this phosphorylation can also be induced through treatment with phorbol 12-myristate acetate (PMA), a PKC activator. Activation of MAPK/ERK was not affected by PKC modulation or by its inhibition. Interestingly, phosphorylation of MAPK/ERK by mAChRs could be blocked by a PKC-ζ (a miroystoilated pseudo substrate of PKC) inhibitor and by high doses of staurosporine (a relatively non-selective protein kinase inhibitor). This pathway involves PI3-K and tyrosine kinases, such as Src, and Erk 1/2 [105, 209]. Cells in the neuroepithelial ventricular zone of the embryonic rat cortex also express the M2 receptor. The presence of M2 induces cell proliferation and accelerates neuronal differentiation.
Adrenergic receptors can transform fibroblasts when actively mutated . Interestingly, transformation by mAChRs was ligand-dependent . Furthermore, some viruses encode constitutively active GPCRs linked to cell proliferation (for a review see [212, 213]), suggesting that signals initiated by GPCRs can be mitogenic.
MAPKs target numerous cellular proteins and transcription factors involved in cell growth and differentiation [214–216]. It is known that GPCRs activate MAPK through the small GTP-binding protein, p21Ras . How p21Ras is activated is still controversial; however, it is likely that transactivation of EGFR upon stimulation of GPCRs participates in p21Ras activation [218, 219]. Indeed, several types of GPCRs including thrombin, endothelin, and angiotensin II receptors have been shown to transactivate EGFR, leading to MAPK activation [220, 221].
The vast majority of the currently described pathways leading to ERK stimulation have been considered as linear. While GPCRs coupled with Gi-protein activate the p21Ras-ERK pathway through the βγ subunit and PI-3 kinase, GPCRs with Gq-protein activate it in a PKC-dependent manner [222, 223]. However, Blaukat et al.  recently showed that GPCRs mediate ERK activation through cooperation of Gi and Gq, suggesting that multiple G-proteins could act in concert to attain full activation of p21Ras-ERK pathway. Muscarinic receptors in many cells have been shown to activate ERK by carbachol, and this is not altered by treatment with pertussis toxin, indicating that Gq-, but not Gi-protein, may be involved in ERK activation [61, 224–229]. Muscarinic receptor activation by carbachol rapidly and transiently stimulates ERK1/2 phosphorylation in many cells in a time- and dose-dependent manner [61, 226–229], as observed in various cell lines [230, 231]. It was shown that the inhibition of PLC led to a total blockade of Ca2+ mobilization induced by AChRs agonists [13, 232]. A role of Ca2+ in this pathway is also supported by the finding that an increase in intracellular Ca2+ caused by thapsigargin [8, 13, 105, 233] is sufficient to induce ERK phosphorylation up to levels similar to those induced by AChRs agonists. The mechanisms by which intracellular Ca2+ stimulates the phosphorylation of ERK1/2 are complex and appear to be dependent on the nature of mAChR subtype coupling to heterotrimeric G proteins. Intracellular Ca2+ can modulate the MAPK cascade, via activation of the monomeric G-protein p21ras [234–236], through two convergent mechanisms; one through the calcium-dependent tyrosine kinase (PYK2) and the other mediated by calmodulin [228, 231, 237]. In T84 colon epithelial cells, which express endogenous M3 mAChR subtypes, increases in [Ca2+]i in response to carbachol activate signaling mechanisms involving calmodulin-, PYK2-, and p60src-mediated transactivation of the EGF receptor . Besides Ca2+, the other downstream pathway induced after PLC activation is the PKC transduction cascade. It was demonstrated that the direct activation of PKC, by the phorbol ester PMA, was sufficient to increase the phosphorylation of ERK1/2 reaching levels similar to those induced by carbachol in FRT cells . However, the carbachol-induced ERK1/2 phosphorylation was not mediated by PKC. These data indicate that the mAChR-induced ERK phosphorylation is mediated by a Ca2+-dependent but PKC-independent mechanism.
Although some data suggest that intracellular Ca2+ partly mediates the activation of ERK1 and ERK2, other intracellular signaling pathways may be involved in the MAPK/ERK activation in undifferentiated cells. Activation of MAPK by GPCRs, including mAChRs, involves phosphorylation of one or more proteins, such as p125FAK, p130cas, or paxillin . Moreover, the Src family of protein tyrosine kinases has been implicated in mAChR-induced ERK activation in different cell lines [240–242]. Further studies are needed to determine the connection between activation of these protein tyrosine kinases and the downstream effects of mAChR after G protein activation.
It has been suggested that carbachol's effects on ERK1 and ERK2 phosphorylation were probably mediated through the activation of protein tyrosine kinases. Furthermore, it has been demonstrated that carbachol-induced ERK activation is dependent on the activity of cytoplasmatic Src-like tyrosine kinase family, since pharmacological inhibition of the Src family of tyrosine kinases with specific PP2 blocks the carbachol-induced MAPK/ERK activation . The Src family of tyrosine kinases has been implicated in the ERK activation by various GPCRs agonists. Recent data suggests that activation of Src tyrosine kinases may lead to the phosphorylation of the adaptor protein Shc and the recruitment of Grb/Sos complex to the plasma membrane, resulting in the activation of the ERK pathway [223, 243].
Signaling pathways of nAChRs involved in proliferation and neuronal differentiation
Microglia express α7 nAChRs , and stimulation of α7 nAChRs promotes anti-inflammatory pathways and blunts the response of migroglia to lipopolysaccaride , suggesting that nAChRs may have a role in controlling localized brain inflammation. Nicotinic receptors are also expressed on O2A oligodendrocyte precursors, but are not detectable after induction of differentiation, indicating that nAChR expression is developmentally controlled in these cells . Although the physiological functions of nAChRs in O2A oligodendrocyte precursors are not understood, data suggest that activation of nAChRs might control migration, survival and differentiation in these cells .
It has been found that in non-neuronal tissues nicotine induces the secretion of growth factors like bFGF, TGF-α, VEGF, and PDGF  Nicotine also upregulates expression of the calpain family of proteins  as well as COX-2 and VEGFR-2 , activating the Raf/MAPK kinase/ERK pathway . Since nAChRs do not have intrinsic tyrosine kinase activity , the molecular mechanisms underlying its effects on proliferation remain unclear. It was demonstrated that nicotine-mediated induction of cell proliferation involves recruitment of β-arrestin, which facilitates the activation of Src. This in turn leads to binding of Raf-1 kinase to Rb, leading to cell cycle entry . Dasgupta and coworkers demonstrated that human non-small cell lung cancer (NSCLC) tumor tissues had high levels of Rb-Raf-1 complexes in tumors relative to adjacent normal lung tissue, suggesting that perhaps the Rb-Raf-1 pathway contributes to the genesis of these tumors. Furthermore, chromatin IP (ChIP) analysis of human NSCLC tumor samples demonstrated increased recruitment of E2F1 and Raf-1 to proliferative promoters like cdc6 and cdc25A. These results suggest that binding of β-arrestin to nAChRs is an early and critical event in the initiation of nicotine-induced mitogenesis. The subsequent steps resemble growth factor-induced cell proliferation, as they include activation of Src, association of Rb to Raf-1, inactivation of Rb, and enhanced recruitment of E2F1 and Raf-1 to promoters of genes that induce proliferation . These events are likely to contribute to the growth and progression of tumoral cells.
Therapeutic uses of cholinergic receptor modulators in stem cell specification
In vivo proliferation, differentiation, and genetic modification of neural stem cell progeny
As previously demonstrated [8, 13], AChRs have different roles on proliferation in embryonic and neural stem cells. In embryonic cells, nAChRs decrease proliferation. Conversely, neural stem cells and their progeny can be induced to proliferate in vivo by administering α7 agonists . To initiate neuronal differentiation, agonists for the Gαi-coupled mAChRs, such as the M2 subtype, could be used for treatment. These pharmacological agents include any substance that acts through AChR activation or through pathways activated by them. The examples described here to modulate proliferation, differentiation, and genetic modification of neural stem cells in vitro can be adapted to in vivo techniques. Such in vivo manipulation and modification of these cells allows cells lost due to injury or disease to be endogenously replaced. This would abolish the need for transplanting foreign cells into a patient. Additionally, cells can be modified or genetically engineered in vivo so that they express various biological agents useful in the treatment of neurological disorders. However, fine control of muscarinic signaling requires compounds that selectively modulate specific muscarinic receptor subtypes. Unfortunately, such drugs have not been discovered yet. M1 muscarinic agonists such as arecoline have also been found to be weak agonists of M2 and M3 subtypes, and are not very effective in treating cognitive impairment, most likely because of dose-limiting side effects [254, 255]. Selective muscarinic agonists for M5 and M2 subtypes could be used both as pharmacological tools and as therapeutic agents , as M5 and M2 mediate most of the muscarinic [Ca2+]i-response and seem to control proliferation and differentiation induction, respectively.
Treatment with nicotinic receptor agonists also has therapeutic potential, similarly to muscarinic agonists. However, nAChR agonists which bind the same site as ACh are not a viable solution, for ACh not only activates, but also blocks receptor activity through desensitization  and uncompetitive blockade [for review see ]. Furthermore, prolonged activation appears to induce a long-lasting inactivation. Therefore, agonists of ACh may reduce or enhance receptor activation. In nAChRs, desensitization generally limits the duration of current during agonist application . However, positive allosteric modulators can enhance the efficacy of agonists at nicotinic receptors. It is believed that such compounds would be useful for treatment of conditions associated with decreased nicotinic transmission. In a therapeutic setting, these compounds could restore normal interneuronal communication without affecting the temporal profile of activation. In addition, they would not produce long-term inactivation, contrary to prolonged application of an agonist.
A naturally existing allosteric modulator of nicotinic transmission is the CGRP (Calcitonin Gene Related Peptide) neuropeptide [259, 260]. Previous reports show that CGRP blocks nAChRs competitively. It is noteworthy to point out that this effect is not mediated by conventional G-protein-coupling , as it was demonstrated that this peptide's activity is contained within the 1–7 N-terminal fragment. Similarly to the native CGRP, CGRP 1–7 shows a rapidly developing, competitive antagonism which is readily reversible after washout . Intriguingly, some CGRP fragments quickly and reversibly enhance responses mediated by the activation of native neuronal nAChRs . Mutant versions of the CGRP peptide fragment can be used as neuronal nAChRs enhancers, as in the absence of nAChR activation these peptides were inactive .
The CGRP 1–6 peptide did not modify the muscle-type nicotinic receptor responses, indicating its selectivity for neuronal receptors. This finding suggests that certain peptide derivatives shorter than CGRP 1–7 exert an unusual action, involving an apparently competitive modulation of the agonist-binding site. CGRP 1–6 and its derivatives may be used for the treatment of symptoms of neurological diseases associated with functional deficits of nAChRs and may be used as stem cell neuronal differentiation enhancers.
Interestingly, nicotine has been shown to protect cells from apoptosis induced by anticancer drugs. The acquisition of drug resistance is a considerable challenge in cancer therapy, and nAChR antagonists could be potentially used in combination with established chemotherapeutic drugs to enhance the therapeutic response to chemotherapy. The bioactivity of nAChR antagonists, however, has yet to be tested in animal models. Carefully designed animal studies are essential to investigate the potential side effects of nAChR antagonists on the brain, central nervous system, immune cells and muscle cells, all of which express high levels of nicotinic receptors.
The study of the roles of nAChRs in development and progression of cancer and stem cells differentiation provides novel opportunities for the prevention and therapy of cancer and degenerative disorders. However, it is important to consider that vital cell and organ functions are regulated by these receptors. Antagonists for α7 nAChR may successfully block cancer cells and promote proliferation of stem cells without cytotoxicity to normal control cells in vitro, but in vivo it would induce adverse effects on the control of inflammatory reactions and the regulation of respiratory and cardiovascular functions, and may also lead to psychiatric symptoms [22, 168, 263].
Blockers of Ca2+ channels are known for their anti-proliferative properties and might be an alternative because they can desensitize the hyperactive α7 nAChR (Figure 1). However, experimental findings appear to be divergent and depend on the cell type and mode of administration used. Among the calcium channel inhibitors, L- and T-type calcium blockers, were reported to inhibit neuronal differentiation [12, 264–266], but have limited effect on other cell types. Mibefradil, a selective blocker of T-type channels, has significant anti-proliferative action in various cell types in vitro as well as in vivo [267, 268]. The non-selective calcium blocker amlodipine is also a very effective protector of neuronal cells [269–271]. Calcium channel blockers induce a rapid decrease in intracellular Ca2+, even in cells lacking depolarization-induced calcium flux [272, 273]. These observations suggest that amlodipine inhibits cell proliferation through intracellular signaling pathways rather than through inhibition of Ca2+ entry channels.
Another possible pharmacological treatment is the use of SluRP1, a drug that reduces the responsiveness of α7nAChR to agonists. SluRP1 may have an effect similar to that of voltage-gated Ca2+ channels blockers . However, any attempt to prevent or treat cancer by targeting nAChRs must be based on the identification of molecular markers. The goal of this strategy is the restoration of balance between stimulatory and inhibitory signaling and not complete blockade of a given pathway.
Nicotinic signaling in non-neuronal cells has huge implications for cell fate and survival. Research in nAChR signaling networks will be especially relevant to stem cell production in a large scale and cancer treatment. Future studies will need to define both the function of different nAChR subtypes in non-neuronal cells and the downstream signaling pathways that underlie the proliferative and anti-apoptotic activities of nicotine.
Similarly to nicotinic signaling, the mechanisms that underlie the pro-mitogenic effects of muscarinic receptor stimulation have not yet been studied in detail. However, several intracellular signaling pathways that regulate the synergistic mitogenic interaction of other GPCR agonists with growth factors in neural progenitor cells have been identified (Figures 1 and 3). These pathways are not the same for every GPCR agonist The GPCRs M1 and M3 increase EGF-induced proliferation through a pathway involving Gβγ, phosphatidylinositol-3-kinase, Akt and PKC [105, 238]. Muscarinic stimulation of MAPK activity and proliferation is prevented both by the intracellular Ca2+ chelator BAPTA-AM and by a reduction in extracellular Ca2+ with EGTA. This suggests that increases in intracellular calcium are essential, and may stimulate Pyk2 phosphorylation and then activate the MAPK signaling pathway . PKC also regulates p42/p44 MAP kinase activation by muscarinic receptor agonists in neuronal progenitor cells .
There is a growing body of evidence indicating that nicotinic and muscarinic receptors play important roles in stem cell differentiation and physiology. The disruption of developmental patterns and of normal function is often correlated with pathological conditions. Therefore, the controlled manipulation of ACh function may lead to novel therapies. Strikingly, studies have revealed that drugs currently used to treat disorders such as Alzheimer's disease and depression, increase adult neurogenesis, which may be the mechanism mediating the activity of these drugs. However, some of these studies are controversial, and remain to be confirmed. Hence, the role of neurogenesis in treating central nervous system disorders, as well as the effects of drugs on embryonic and adult stem cells' neuronal differentiation remain areas of active research. Discriminating specific contributions of nAChR and mAChR signaling for the control of phenotypic features as specialized structural and functional behaviors is a great challenge and has undeniable potential regarding future applications.
This work was supported by Instituto do Milenio/CNPq-MCT and Instituto Nacional de Ciência e Tecnologia de Nanomateriais de Carbono, CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), Brazil. R.R.R is grateful for grants from CNPq, and FAPEMIG (Fundação de Amparo à Pesquisa do Estado de Minas Gerais), Brazil. English editing has been performed throughout the text by native English speaker Dra. Elizabeth Speed.
- Horiuchi Y, Kimura R, Kato N, Fujii T, Seki M, Endo T, Kato T, Kawashima K: Evolutional study on acetylcholine expression. Life Sci. 2003, 72: 1745-1756.PubMedGoogle Scholar
- Grando SA: Biological functions of keratinocyte cholinergic receptors. J Investig Dermatol Symp Proc. 1997, 2: 41-48.PubMedGoogle Scholar
- Wessler I, Kirkpatrick CJ, Racke K: The cholinergic 'pitfall': acetylcholine, a universal cell molecule in biological systems, including humans. Clin Exp Pharmacol Physiol. 1999, 26: 198-205.PubMedGoogle Scholar
- Kawashima K, Fujii T: Extraneuronal cholinergic system in lymphocytes. Pharmacol Ther. 2000, 86: 29-48.PubMedGoogle Scholar
- Wessler I, Reinheimer T, Kilbinger H, Bittinger F, Kirkpatrick CJ, Saloga J, Knop J: Increased acetylcholine levels in skin biopsies of patients with atopic dermatitis. Life Sci. 2003, 72: 2169-2172.PubMedGoogle Scholar
- Tobin AB, Budd DC: The anti-apoptotic response of the Gq/11-coupled muscarinic receptor family. Biochem Soc Trans. 2003, 31: 1182-1185.PubMedGoogle Scholar
- Kawashima K, Fujii T: Expression of non-neuronal acetylcholine in lymphocytes and its contribution to the regulation of immune function. Front Biosci. 2004, 9: 2063-2085.PubMedGoogle Scholar
- Resende RR, Alves AS, Britto LR, Ulrich H: Role of acetylcholine receptors in proliferation and differentiation of P19 embryonal carcinoma cells. Exp Cell Res. 2008, 314: 1429-1443.PubMedGoogle Scholar
- Williams BP, Milligan CJ, Street M, Hornby FM, Deuchars J, Buckley NJ: Transcription of the M1 muscarinic receptor gene in neurons and neuronal progenitors of the embryonic rat forebrain. J Neurochem. 2004, 88: 70-77.PubMedGoogle Scholar
- Wessler I, Kirkpatrick CJ: Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol. 2008, 154: 1558-1571.PubMed CentralPubMedGoogle Scholar
- Martins AH, Resende RR, Majumder P, Faria M, Casarini DE, Tarnok A, Colli W, Pesquero JB, Ulrich H: Neuronal differentiation of P19 embryonal carcinoma cells modulates kinin B2 receptor gene expression and function. J Biol Chem. 2005, 280: 19576-19586.PubMedGoogle Scholar
- Resende RR, Majumder P, Gomes KN, Britto LR, Ulrich H: P19 embryonal carcinoma cells as in vitro model for studying purinergic receptor expression and modulation of N-methyl-D-aspartate-glutamate and acetylcholine receptors during neuronal differentiation. Neuroscience. 2007, 146: 1169-1181.PubMedGoogle Scholar
- Resende RR, Gomes KN, Adhikari A, Britto LR, Ulrich H: Mechanism of acetylcholine-induced calcium signaling during neuronal differentiation of P19 embryonal carcinoma cells in vitro. Cell Calcium. 2008, 43: 107-121.PubMedGoogle Scholar
- Buznikov GA, Shmukler YB, Lauder JM: From oocyte to neuron: do neurotransmitters function in the same way throughout development?. Cell Mol Neurobiol. 1996, 16: 537-559.PubMedGoogle Scholar
- Levitt P, Harvey JA, Friedman E, Simansky K, Murphy EH: New evidence for neurotransmitter influences on brain development. Trends Neurosci. 1997, 20: 269-274.PubMedGoogle Scholar
- Bignami F, Bevilacqua P, Biagioni S, De Jaco A, Casamenti F, Felsani A, Augusti-Tocco G: Cellular acetylcholine content and neuronal differentiation. J Neurochem. 1997, 69: 1374-1381.PubMedGoogle Scholar
- Schuller HM: Cell type specific, receptor-mediated modulation of growth kinetics in human lung cancer cell lines by nicotine and tobacco-related nitrosamines. Biochem Pharmacol. 1989, 38: 3439-3442.PubMedGoogle Scholar
- Maneckjee R, Minna JD: Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines. Proc Natl Acad Sci USA. 1990, 87: 3294-3298.PubMed CentralPubMedGoogle Scholar
- Lindstrom JM: Acetylcholine receptors and myasthenia. Muscle Nerve. 2000, 23: 453-477.PubMedGoogle Scholar
- Changeux J, Edelstein SJ: Allosteric mechanisms in normal and pathological nicotinic acetylcholine receptors. Curr Opin Neurobiol. 2001, 11: 369-377.PubMedGoogle Scholar
- Hogg RC, Raggenbass M, Bertrand D: Nicotinic acetylcholine receptors: from structure to brain function. Rev Physiol Biochem Pharmacol. 2003, 147: 1-46.PubMedGoogle Scholar
- Gotti C, Clementi F: Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol. 2004, 74: 363-396.PubMedGoogle Scholar
- McGehee DS, Role LW: Presynaptic ionotropic receptors. Curr Opin Neurobiol. 1996, 6: 342-349.PubMedGoogle Scholar
- Koh DC, Armugam A, Jeyaseelan K: Snake venom components and their applications in biomedicine. Cell Mol Life Sci. 2006, 63: 3030-3041.PubMedGoogle Scholar
- Portugal GS, Gould TJ: Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: converging evidence from human and animal research. Behav Brain Res. 2008, 193: 1-16.PubMed CentralPubMedGoogle Scholar
- Changeux JP, Edelstein SJ: Allosteric receptors after 30 years. Neuron. 1998, 21: 959-980.PubMedGoogle Scholar
- Seguela P, Wadiche J, Dineley-Miller K, Dani JA, Patrick JW: Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium. J Neurosci. 1993, 13: 596-604.PubMedGoogle Scholar
- Broide RS, Leslie FM: The alpha7 nicotinic acetylcholine receptor in neuronal plasticity. Mol Neurobiol. 1999, 20: 1-16.PubMedGoogle Scholar
- Forster GL, Yeomans JS, Takeuchi J, Blaha CD: M5 muscarinic receptors are required for prolonged accumbal dopamine release after electrical stimulation of the pons in mice. J Neurosci. 2002, 22: RC190-PubMedGoogle Scholar
- Yeomans J, Forster G, Blaha C: M5 muscarinic receptors are needed for slow activation of dopamine neurons and for rewarding brain stimulation. Life Sci. 2001, 68: 2449-2456.PubMedGoogle Scholar
- Basile AS, Fedorova I, Zapata A, Liu X, Shippenberg T, Duttaroy A, Yamada M, Wess J: Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia. Proc Natl Acad Sci USA. 2002, 99: 11452-11457.PubMed CentralPubMedGoogle Scholar
- Wang H, Ng K, Hayes D, Gao X, Forster G, Blaha C, Yeomans J: Decreased amphetamine-induced locomotion and improved latent inhibition in mice mutant for the M5 muscarinic receptor gene found in the human 15q schizophrenia region. Neuropsychopharmacology. 2004, 29: 2126-2139.PubMedGoogle Scholar
- Tzavara ET, Bymaster FP, Davis RJ, Wade MR, Perry KW, Wess J, McKinzie DL, Felder C, Nomikos GG: M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies. Faseb J. 2004, 18: 1410-1412.PubMedGoogle Scholar
- Di Cara B, Panayi F, Gobert A, Dekeyne A, Sicard D, De Groote L, Millan MJ: Activation of dopamine D1 receptors enhances cholinergic transmission and social cognition: a parallel dialysis and behavioural study in rats. Int J Neuropsychopharmacol. 2007, 10: 383-399.PubMedGoogle Scholar
- Hegde SS, Mammen M, Jasper JR: Antimuscarinics for the treatment of overactive bladder: current options and emerging therapies. Curr Opin Investig Drugs. 2004, 5: 40-49.PubMedGoogle Scholar
- Racke K, Matthiesen S: The airway cholinergic system: physiology and pharmacology. Pulm Pharmacol Ther. 2004, 17: 181-198.PubMedGoogle Scholar
- Keam SJ, Keating GM: Tiotropium bromide. Treat Respir Med. 2004, 3: 247-268.PubMedGoogle Scholar
- Terry AV Jr, Buccafusco JJ: The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther. 2003, 306: 821-827.PubMedGoogle Scholar
- Bartus RT: On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol. 2000, 163: 495-529.PubMedGoogle Scholar
- Fox RI: Sjogren's syndrome: evolving therapies. Expert Opin Investig Drugs. 2003, 12: 247-254.PubMedGoogle Scholar
- Roman GC: Cholinergic dysfunction in vascular dementia. Curr Psychiatry Rep. 2005, 7: 18-26.PubMedGoogle Scholar
- Felder CC, Bymaster FP, Ward J, DeLapp N: Therapeutic opportunities for muscarinic receptors in the central nervous system. J Med Chem. 2000, 43: 4333-4353.PubMedGoogle Scholar
- Birdsall NJ, Lazareno S, Popham A, Saldanha J: Multiple allosteric sites on muscarinic receptors. Life Sci. 2001, 68: 2517-2524.PubMedGoogle Scholar
- Eglen RM, Choppin A, Watson N: Therapeutic opportunities from muscarinic receptor research. Trends Pharmacol Sci. 2001, 22: 409-414.PubMedGoogle Scholar
- Matsui M, Yamada S, Oki T, Manabe T, Taketo MM, Ehlert FJ: Functional analysis of muscarinic acetylcholine receptors using knockout mice. Life Sci. 2004, 75: 2971-2981.PubMedGoogle Scholar
- Slotkin TA, Cousins MM, Seidler FJ: Administration of nicotine to adolescent rats evokes regionally selective upregulation of CNS alpha 7 nicotinic acetylcholine receptors. Brain Res. 2004, 1030: 159-163.PubMedGoogle Scholar
- Zoli M, Le Novere N, Hill JA Jr, Changeux JP: Developmental regulation of nicotinic ACh receptor subunit mRNAs in the rat central and peripheral nervous systems. J Neurosci. 1995, 15: 1912-1939.PubMedGoogle Scholar
- Aubert I, Cecyre D, Gauthier S, Quirion R: Comparative ontogenic profile of cholinergic markers, including nicotinic and muscarinic receptors, in the rat brain. J Comp Neurol. 1996, 369: 31-55.PubMedGoogle Scholar
- Court JA, Lloyd S, Johnson M, Griffiths M, Birdsall NJ, Piggott MA, Oakley AE, Ince PG, Perry EK, Perry RH: Nicotinic and muscarinic cholinergic receptor binding in the human hippocampal formation during development and aging. Brain Res Dev Brain Res. 1997, 101: 93-105.PubMedGoogle Scholar
- Torrao AS, Carmona FM, Lindstrom J, Britto LR: Expression of cholinergic system molecules during development of the chick nervous system. Brain Res Dev Brain Res. 2000, 124: 81-92.PubMedGoogle Scholar
- Atluri P, Fleck MW, Shen Q, Mah SJ, Stadfelt D, Barnes W, Goderie SK, Temple S, Schneider AS: Functional nicotinic acetylcholine receptor expression in stem and progenitor cells of the early embryonic mouse cerebral cortex. Dev Biol. 2001, 240: 143-156.PubMedGoogle Scholar
- Oppitz M, Mobus V, Brock S, Drews U: Muscarinic receptors in cell lines from ovarian carcinoma: negative correlation with survival of patients. Gynecol Oncol. 2002, 85: 159-164.PubMedGoogle Scholar
- Hoogduijn MJ, Cheng A, Genever PG: Functional Nicotinic and Muscarinic Receptors on Mesenchymal Stem Cells. Stem Cells Dev. 2008,Google Scholar
- Greco SJ, Zhou C, Ye JH, Rameshwar P: An interdisciplinary approach and characterization of neuronal cells transdifferentiated from human mesenchymal stem cells. Stem Cells Dev. 2007, 16: 811-826.PubMedGoogle Scholar
- Zhao WQ, Alkon DL, Ma W: c-Src protein tyrosine kinase activity is required for muscarinic receptor-mediated DNA synthesis and neurogenesis via ERK1/2 and c-AMP-responsive element-binding protein signaling in neural precursor cells. J Neurosci Res. 2003, 72: 334-342.PubMedGoogle Scholar
- Bernardini N, Levey AI, Augusti-Tocco G: Rat dorsal root ganglia express m1–m4 muscarinic receptor proteins. J Peripher Nerv Syst. 1999, 4: 222-232.PubMedGoogle Scholar
- Williams CL, Hayes VY, Hummel AM, Tarara JE, Halsey TJ: Regulation of E-cadherin-mediated adhesion by muscarinic acetylcholine receptors in small cell lung carcinoma. J Cell Biol. 1993, 121: 643-654.PubMedGoogle Scholar
- Boss A, Oppitz M, Drews U: Muscarinic cholinergic receptors in the human melanoma cell line SK-Mel 28: modulation of chemotaxis. Clin Exp Dermatol. 2005, 30: 557-564.PubMedGoogle Scholar
- Rimmaudo LE, de la Torre E, Sacerdote de Lustig E, Sales ME: Muscarinic receptors are involved in LMM3 tumor cells proliferation and angiogenesis. Biochem Biophys Res Commun. 2005, 334: 1359-1364.PubMedGoogle Scholar
- Newman MB, Misiuta I, Willing AE, Zigova T, Karl RC, Borlongan CV, Sanberg PR: Tumorigenicity issues of embryonic carcinoma-derived stem cells: relevance to surgical trials using NT2 and hNT neural cells. Stem Cells Dev. 2005, 14: 29-43.PubMedGoogle Scholar
- Wu EH, Wong YH: Activation of muscarinic M4 receptor augments NGF-induced pro-survival Akt signaling in PC12 cells. Cell Signal. 2006, 18: 285-293.PubMedGoogle Scholar
- Pollett JB, Corsi KA, Weiss KR, Cooper GM, Barry DA, Gharaibeh B, Huard J: Malignant transformation of multipotent muscle-derived cells by concurrent differentiation signals. Stem Cells. 2007, 25: 2302-2311.PubMedGoogle Scholar
- Song P, Sekhon HS, Lu A, Arredondo J, Sauer D, Gravett C, Mark GP, Grando SA, Spindel ER: M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion. Cancer Res. 2007, 67: 3936-3944.PubMedGoogle Scholar
- Janulis M, Silberman S, Ambegaokar A, Gutkind JS, Schultz RM: Role of mitogen-activated protein kinases and c-Jun/AP-1 trans-activating activity in the regulation of protease mRNAs and the malignant phenotype in NIH 3T3 fibroblasts. J Biol Chem. 1999, 274: 801-813.PubMedGoogle Scholar
- Blanco M, Robinson MJ: Muscarinic M3 acetylcholine receptor immunostaining in paraffin-embedded normal and neoplastic prostatic gland tissue. Ann Diagn Pathol. 2004, 8: 333-336.PubMedGoogle Scholar
- Espanol AJ, Sales ME: Different muscarinc receptors are involved in the proliferation of murine mammary adenocarcinoma cell lines. Int J Mol Med. 2004, 13: 311-317.PubMedGoogle Scholar
- Metzger M, Just L, Boss A, Drews U: Identification and functional characterization of the muscarinic receptor M3 in the human keratinocyte cell line HaCaT. Cells Tissues Organs. 2005, 180: 96-105.PubMedGoogle Scholar
- Shin S, Dalton S, Stice SL: Human motor neuron differentiation from human embryonic stem cells. Stem Cells Dev. 2005, 14: 266-269.PubMedGoogle Scholar
- Hoogduijn MJCA, Genever PG: Functional Nicotinic and Muscarinic Receptors on Mesenchymal Stem Cells. Stem Cells and Development. 2008Google Scholar
- Inoue M, Yoshii M: Modulation of ion channels by somatostatin and acetylcholine. Prog Neurobiol. 1992, 38: 203-230.PubMedGoogle Scholar
- van Koppen CJ, Kaiser B: Regulation of muscarinic acetylcholine receptor signaling. Pharmacol Ther. 2003, 98: 197-220.PubMedGoogle Scholar
- Williams CL: Muscarinic signaling in carcinoma cells. Life Sci. 2003, 72: 2173-2182.PubMedGoogle Scholar
- Gutkind JS, Crespo P, Xu N, Teramoto H, Coso OA: The pathway connecting m2 receptors to the nucleus involves small GTP-binding proteins acting on divergent MAP kinase cascades. Life Sci. 1997, 60: 999-1006.PubMedGoogle Scholar
- Nicke B, Detjen K, Logsdon CD: Muscarinic cholinergic receptors activate both inhibitory and stimulatory growth mechanisms in NIH3T3 cells. J Biol Chem. 1999, 274: 21701-21706.PubMedGoogle Scholar
- Burdon D, Patel R, Challiss RA, Blank JL: Growth inhibition by the muscarinic M(3) acetylcholine receptor: evidence for p21(Cip1/Waf1) involvement in G(1) arrest. Biochem J. 2002, 367: 549-559.PubMed CentralPubMedGoogle Scholar
- Brown JH, Sah V, Moskowitz S, Ramirez T, Collins L, Post G, Goldstein D: Pathways and roadblocks in muscarinic receptor-mediated growth regulation. Life Sci. 1997, 60: 1077-1084.PubMedGoogle Scholar
- Shafer SH, Williams CL: Elevated Rac1 activity changes the M3 muscarinic acetylcholine receptor-mediated inhibition of proliferation to induction of cell death. Mol Pharmacol. 2004, 65: 1080-1091.PubMedGoogle Scholar
- Lindenboim L, Pinkas-Kramarski R, Sokolovsky M, Stein R: Activation of muscarinic receptors inhibits apoptosis in PC12M1 cells. J Neurochem. 1995, 64: 2491-2499.PubMedGoogle Scholar
- Leloup C, Michaelson DM, Fisher A, Hartmann T, Beyreuther K, Stein R: M1 muscarinic receptors block caspase activation by phosphoinositide 3-kinase- and MAPK/ERK-independent pathways. Cell Death Differ. 2000, 7: 825-833.PubMedGoogle Scholar
- De Sarno P, Shestopal SA, King TD, Zmijewska A, Song L, Jope RS: Muscarinic receptor activation protects cells from apoptotic effects of DNA damage, oxidative stress, and mitochondrial inhibition. J Biol Chem. 2003, 278: 11086-11093.PubMed CentralPubMedGoogle Scholar
- Serobyan N, Orlovskaya I, Kozlov V, Khaldoyanidi SK: Exposure to nicotine during gestation interferes with the colonization of fetal bone marrow by hematopoietic stem/progenitor cells. Stem Cells Dev. 2005, 14: 81-91.PubMedGoogle Scholar
- Budd DC, Spragg EJ, Ridd K, Tobin AB: Signalling of the M3-muscarinic receptor to the anti-apoptotic pathway. Biochem J. 2004, 381: 43-49.PubMed CentralPubMedGoogle Scholar
- Budd DC, McDonald J, Emsley N, Cain K, Tobin AB: The C-terminal tail of the M3-muscarinic receptor possesses anti-apoptotic properties. J Biol Chem. 2003, 278: 19565-19573.PubMedGoogle Scholar
- Tipton DA, Dabbous MK: Effects of nicotine on proliferation and extracellular matrix production of human gingival fibroblasts in vitro. J Periodontol. 1995, 66: 1056-1064.PubMedGoogle Scholar
- Peng X, Gerzanich V, Anand R, Wang F, Lindstrom J: Chronic nicotine treatment up-regulates alpha3 and alpha7 acetylcholine receptor subtypes expressed by the human neuroblastoma cell line SH-SY5Y. Mol Pharmacol. 1997, 51: 776-784.PubMedGoogle Scholar
- Wang F, Nelson ME, Kuryatov A, Olale F, Cooper J, Keyser K, Lindstrom J: Chronic nicotine treatment up-regulates human alpha3 beta2 but not alpha3 beta4 acetylcholine receptors stably transfected in human embryonic kidney cells. J Biol Chem. 1998, 273: 28721-28732.PubMedGoogle Scholar
- Giannopoulou C, Roehrich N, Mombelli A: Effect of nicotine-treated epithelial cells on the proliferation and collagen production of gingival fibroblasts. J Clin Periodontol. 2001, 28: 769-775.PubMedGoogle Scholar
- Varker KA, Williams CL: Involvement of the muscarinic acetylcholine receptor in inhibition of cell migration. Biochem Pharmacol. 2002, 63: 597-605.PubMedGoogle Scholar
- Chernyavsky AI, Arredondo J, Wess J, Karlsson E, Grando SA: Novel signaling pathways mediating reciprocal control of keratinocyte migration and wound epithelialization through M3 and M4 muscarinic receptors. J Cell Biol. 2004, 166: 261-272.PubMed CentralPubMedGoogle Scholar
- Yoon SY, Kim HW, Roh DH, Kwon YB, Han HJ, Beitz AJ, Lee JH: Intrathecal clonidine suppresses zymosan-induced peripheral leukocyte migration in a mouse air pouch model via activation of spinal muscarinic type 2 receptors and sympathoadrenal medullary activity. Neuropharmacology. 2006, 51: 829-837.PubMedGoogle Scholar
- Oppitz M, Mack A, Drews U: Ca2+-mobilization and cell contraction after muscarinic cholinergic stimulation of the chick embryo lens. Invest Ophthalmol Vis Sci. 2003, 44: 4813-4819.PubMedGoogle Scholar
- Drews U, Mengis W: Contraction wave in the chick blastoderm induced by muscarinic stimulation. Anat Embryol (Berl). 1990, 182: 447-454.Google Scholar
- Sailer M, Oppitz M, Drews U: Induction of cellular contractions in the human melanoma cell line SK-mel 28 after muscarinic cholinergic stimulation. Anat Embryol (Berl). 2000, 201: 27-37.Google Scholar
- Koh JY, Palmer E, Cotman CW: Activation of the metabotropic glutamate receptor attenuates N-methyl-D-aspartate neurotoxicity in cortical cultures. Proc Natl Acad Sci USA. 1991, 88: 9431-9435.PubMed CentralPubMedGoogle Scholar
- Yan GM, Lin SZ, Irwin RP, Paul SM: Activation of muscarinic cholinergic receptors blocks apoptosis of cultured cerebellar granule neurons. Mol Pharmacol. 1995, 47: 248-257.PubMedGoogle Scholar
- Marte BM, Downward J: PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci. 1997, 22: 355-358.PubMedGoogle Scholar
- Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME: Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science. 1997, 275: 661-665.PubMedGoogle Scholar
- Kulik G, Klippel A, Weber MJ: Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol. 1997, 17: 1595-1606.PubMed CentralPubMedGoogle Scholar
- Murga C, Laguinge L, Wetzker R, Cuadrado A, Gutkind JS: Activation of Akt/protein kinase B by G protein-coupled receptors. J Biol Chem. 1998, 273: 19080-19085.PubMedGoogle Scholar
- Desdouits-Magnen J, Desdouits F, Takeda S, Syu LJ, Saltiel AR, Buxbaum JD, Czernik AJ, Nairn AC, Greengard P: Regulation of secretion of Alzheimer amyloid precursor protein by the mitogen-activated protein kinase cascade. J Neurochem. 1998, 70: 524-530.PubMedGoogle Scholar
- Ueda H, Morishita R, Narumiya S, Kato K, Asano T: Galphaq/11 signaling induces apoptosis through two pathways involving reduction of Akt phosphorylation and activation of RhoA in HeLa cells. Exp Cell Res. 2004, 298: 207-217.PubMedGoogle Scholar
- Novakova J, Mikasova L, Machova E, Lisa V, Dolezal V: Chronic treatment with amyloid beta(1–42) inhibits non-cholinergic high-affinity choline transport in NG108-15 cells through protein kinase C signaling. Brain Res. 2005, 1062: 101-110.PubMedGoogle Scholar
- Kodaira M, Kajimura M, Takeuchi K, Lin S, Hanai H, Kaneko E: Functional muscarinic m3 receptor expressed in gastric cancer cells stimulates tyrosine phosphorylation and MAP kinase. J Gastroenterol. 1999, 34: 163-171.PubMedGoogle Scholar
- Ukegawa JI, Takeuchi Y, Kusayanagi S, Mitamura K: Growth-promoting effect of muscarinic acetylcholine receptors in colon cancer cells. J Cancer Res Clin Oncol. 2003, 129: 272-278.PubMedGoogle Scholar
- Jimenez E, Montiel M: Activation of MAP kinase by muscarinic cholinergic receptors induces cell proliferation and protein synthesis in human breast cancer cells. J Cell Physiol. 2005, 204: 678-686.PubMedGoogle Scholar
- Song P, Sekhon HS, Jia Y, Keller JA, Blusztajn JK, Mark GP, Spindel ER: Acetylcholine is synthesized by and acts as an autocrine growth factor for small cell lung carcinoma. Cancer Res. 2003, 63: 214-221.PubMedGoogle Scholar
- Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995, 270: 1326-1331.PubMedGoogle Scholar
- Anderson CN, Tolkovsky AM: A role for MAPK/ERK in sympathetic neuron survival: protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J Neurosci. 1999, 19: 664-673.PubMedGoogle Scholar
- Yao R, Cooper GM: Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science. 1995, 267: 2003-2006.PubMedGoogle Scholar
- Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC: Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998, 282: 1318-1321.PubMedGoogle Scholar
- Page C, Lin HJ, Jin Y, Castle VP, Nunez G, Huang M, Lin J: Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. Anticancer Res. 2000, 20: 407-416.PubMedGoogle Scholar
- Henshall DC, Araki T, Schindler CK, Lan JQ, Tiekoter KL, Taki W, Simon RP: Activation of Bcl-2-associated death protein and counter-response of Akt within cell populations during seizure-induced neuronal death. J Neurosci. 2002, 22: 8458-8465.PubMedGoogle Scholar
- del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G: Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science. 1997, 278: 687-689.PubMedGoogle Scholar
- Kennedy SG, Wagner AJ, Conzen SD, Jordan J, Bellacosa A, Tsichlis PN, Hay N: The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 1997, 11: 701-713.PubMedGoogle Scholar
- Cui QL, Fogle E, Almazan G: Muscarinic acetylcholine receptors mediate oligodendrocyte progenitor survival through Src-like tyrosine kinases and PI3K/Akt pathways. Neurochem Int. 2006, 48: 383-393.PubMedGoogle Scholar
- Datta SR, Brunet A, Greenberg ME: Cellular survival: a play in three Akts. Genes Dev. 1999, 13: 2905-2927.PubMedGoogle Scholar
- Janssens V, Goris J: Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J. 2001, 353: 417-439.PubMed CentralPubMedGoogle Scholar
- Testa JR, Bellacosa A: AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA. 2001, 98: 10983-10985.PubMed CentralPubMedGoogle Scholar
- Song G, Ouyang G, Bao S: The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005, 9: 59-71.PubMedGoogle Scholar
- Yan CY, Greene LA: Prevention of PC12 cell death by N-acetylcysteine requires activation of the Ras pathway. J Neurosci. 1998, 18: 4042-4049.PubMedGoogle Scholar
- Hartfield PJ, Bilney AJ, Murray AW: Neurotrophic factors prevent ceramide-induced apoptosis downstream of c-Jun N-terminal kinase activation in PC12 cells. J Neurochem. 1998, 71: 161-169.PubMedGoogle Scholar
- Pettigrew DB, Li YQ, Kuntz Ct, Crutcher KA: Global expression of NGF promotes sympathetic axonal growth in CNS white matter but does not alter its parallel orientation. Exp Neurol. 2007, 203: 95-109.PubMed CentralPubMedGoogle Scholar
- Ulrich E, Duwel A, Kauffmann-Zeh A, Gilbert C, Lyon D, Rudkin B, Evan G, Martin-Zanca D: Specific TrkA survival signals interfere with different apoptotic pathways. Oncogene. 1998, 16: 825-832.PubMedGoogle Scholar
- Scheid MP, Duronio V: Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: involvement of MEK upstream of Bad phosphorylation. Proc Natl Acad Sci USA. 1998, 95: 7439-7444.PubMed CentralPubMedGoogle Scholar
- Crowder RJ, Freeman RS: Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons. J Neurosci. 1998, 18: 2933-2943.PubMedGoogle Scholar
- Bui NT, Konig HG, Culmsee C, Bauerbach E, Poppe M, Krieglstein J, Prehn JH: p75 neurotrophin receptor is required for constitutive and NGF-induced survival signalling in PC12 cells and rat hippocampal neurones. J Neurochem. 2002, 81: 594-605.PubMedGoogle Scholar
- Zheng WH, Kar S, Quirion R: FKHRL1 and its homologs are new targets of nerve growth factor Trk receptor signaling. J Neurochem. 2002, 80: 1049-1061.PubMedGoogle Scholar
- Rakhit S, Pyne S, Pyne NJ: Nerve growth factor stimulation of p42/p44 mitogen-activated protein kinase in PC12 cells: role of G(i/o), G protein-coupled receptor kinase 2, beta-arrestin I, and endocytic processing. Mol Pharmacol. 2001, 60: 63-70.PubMedGoogle Scholar
- Lou X, Yano H, Lee F, Chao MV, Farquhar MG: GIPC and GAIP form a complex with TrkA: a putative link between G protein and receptor tyrosine kinase pathways. Mol Biol Cell. 2001, 12: 615-627.PubMed CentralPubMedGoogle Scholar
- Kanoh Y, Ishizuka T, Morita H, Ishizawa M, Miura A, Kajita K, Kimura M, Suzuki T, Sakuma H, Yasuda K: Effect of pertussis toxin on insulin-induced signal transduction in rat adipocytes and soleus muscles. Cell Signal. 2000, 12: 223-232.PubMedGoogle Scholar
- Balteskard L, Unneberg K, Mjaaland M, Jenssen TG, Revhaug A: Growth hormone and insulinlike growth factor 1 promote intestinal uptake and hepatic release of glutamine in sepsis. Ann Surg. 1998, 228: 131-139.PubMed CentralPubMedGoogle Scholar
- Kim S, Garcia A, Jackson SP, Kunapuli SP: Insulin-like growth factor-1 regulates platelet activation through PI3-Kalpha isoform. Blood. 2007, 110: 4206-4213.PubMed CentralPubMedGoogle Scholar
- Moughal NA, Waters C, Sambi B, Pyne S, Pyne NJ: Nerve growth factor signaling involves interaction between the Trk A receptor and lysophosphatidate receptor 1 systems: nuclear translocation of the lysophosphatidate receptor 1 and Trk A receptors in pheochromocytoma 12 cells. Cell Signal. 2004, 16: 127-136.PubMedGoogle Scholar
- Piiper A, Zeuzem S: Receptor tyrosine kinases are signaling intermediates of G protein-coupled receptors. Curr Pharm Des. 2004, 10: 3539-3545.PubMedGoogle Scholar
- Natarajan K, Berk BC: Crosstalk coregulation mechanisms of G protein-coupled receptors and receptor tyrosine kinases. Methods Mol Biol. 2006, 332: 51-77.PubMedGoogle Scholar
- Zhao Y, He D, Stern R, Usatyuk PV, Spannhake EW, Salgia R, Natarajan V: Lysophosphatidic acid modulates c-Met redistribution and hepatocyte growth factor/c-Met signaling in human bronchial epithelial cells through PKC delta and E-cadherin. Cell Signal. 2007, 19: 2329-2338.PubMed CentralPubMedGoogle Scholar
- Xie P, Browning DD, Hay N, Mackman N, Ye RD: Activation of NF-kappa B by bradykinin through a Galpha(q)- and Gbeta gamma-dependent pathway that involves phosphoinositide 3-kinase and Akt. J Biol Chem. 2000, 275: 24907-24914.PubMedGoogle Scholar
- Clerk A, Aggeli IK, Stathopoulou K, Sugden PH: Peptide growth factors signal differentially through protein kinase C to extracellular signal-regulated kinases in neonatal cardiomyocytes. Cell Signal. 2006, 18: 225-235.PubMedGoogle Scholar
- Chong ZZ, Lin SH, Li F, Maiese K: The sirtuin inhibitor nicotinamide enhances neuronal cell survival during acute anoxic injury through AKT, BAD, PARP, and mitochondrial associated "anti-apoptotic" pathways. Curr Neurovasc Res. 2005, 2: 271-285.PubMed CentralPubMedGoogle Scholar
- Chong ZZ, Li F, Maiese K: Erythropoietin requires NF-kappaB and its nuclear translocation to prevent early and late apoptotic neuronal injury during beta-amyloid toxicity. Curr Neurovasc Res. 2005, 2: 387-399.PubMed CentralPubMedGoogle Scholar
- Laychock SG, Sessanna SM, Lin MH, Mastrandrea LD: Sphingosine 1-phosphate affects cytokine-induced apoptosis in rat pancreatic islet beta-cells. Endocrinology. 2006, 147: 4705-4712.PubMedGoogle Scholar
- Meyer zu Heringdorf D, Lass H, Kuchar I, Alemany R, Guo Y, Schmidt M, Jakobs KH: Role of sphingosine kinase in Ca(2+) signalling by epidermal growth factor receptor. FEBS Lett. 1999, 461: 217-222.PubMedGoogle Scholar
- Xiang J, Chao DT, Korsmeyer SJ: BAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases. Proc Natl Acad Sci USA. 1996, 93: 14559-14563.PubMed CentralPubMedGoogle Scholar
- Wang NS, Unkila MT, Reineks EZ, Distelhorst CW: Transient expression of wild-type or mitochondrially targeted Bcl-2 induces apoptosis, whereas transient expression of endoplasmic reticulum-targeted Bcl-2 is protective against Bax-induced cell death. J Biol Chem. 2001, 276: 44117-44128.PubMedGoogle Scholar
- Li A, Harris DA: Mammalian prion protein suppresses Bax-induced cell death in yeast. J Biol Chem. 2005, 280: 17430-17434.PubMedGoogle Scholar
- Facchinetti F, Furegato S, Terrazzino S, Leon A: H(2)O(2) induces upregulation of Fas and Fas ligand expression in NGF-differentiated PC12 cells: modulation by cAMP. J Neurosci Res. 2002, 69: 178-188.PubMedGoogle Scholar
- Ulloth JE, Casiano CA, De Leon M: Palmitic and stearic fatty acids induce caspase-dependent and -independent cell death in nerve growth factor differentiated PC12 cells. J Neurochem. 2003, 84: 655-668.PubMed CentralPubMedGoogle Scholar
- Liu XB, Masago R, Kong L, Zhang BX, Masago S, Vela-Roch N, Katz MS, Yeh CK, Zhang GH, Talal N, Dang H: G-protein signaling abnormalities mediated by CD95 in salivary epithelial cells. Cell Death Differ. 2000, 7: 1119-1126.PubMedGoogle Scholar
- Pugazhenthi S, Boras T, O'Connor D, Meintzer MK, Heidenreich KA, Reusch JE: Insulin-like growth factor I-mediated activation of the transcription factor cAMP response element-binding protein in PC12 cells. J Biol Chem. 1999, 274: 2829-2837.PubMedGoogle Scholar
- Zheng WH, Kar S, Quirion R: Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells. J Biol Chem. 2000, 275: 39152-39158.PubMedGoogle Scholar
- Kozma R, Sarner S, Ahmed S, Lim L: Rho family GTPases and neuronal growth cone remodelling: relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol Cell Biol. 1997, 17: 1201-1211.PubMed CentralPubMedGoogle Scholar
- Linseman DA, Heidenreich KA, Fisher SK: Stimulation of M3 muscarinic receptors induces phosphorylation of the Cdc42 effector activated Cdc42Hs-associated kinase-1 via a Fyn tyrosine kinase signaling pathway. J Biol Chem. 2001, 276: 5622-5628.PubMedGoogle Scholar
- Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, et al.: Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 1996, 273: 245-248.PubMedGoogle Scholar
- Wang Y, Yoshioka K, Azam MA, Takuwa N, Sakurada S, Kayaba Y, Sugimoto N, Inoki I, Kimura T, Kuwaki T, Takuwa Y: Class II phosphoinositide 3-kinase alpha-isoform regulates Rho, myosin phosphatase and contraction in vascular smooth muscle. Biochem J. 2006, 394: 581-592.PubMed CentralPubMedGoogle Scholar
- Fromm C, Coso OA, Montaner S, Xu N, Gutkind JS: The small GTP-binding protein Rho links G protein-coupled receptors and Galpha12 to the serum response element and to cellular transformation. Proc Natl Acad Sci USA. 1997, 94: 10098-10103.PubMed CentralPubMedGoogle Scholar
- Shaw S, Bencherif M, Marrero MB: Janus kinase 2, an early target of alpha 7 nicotinic acetylcholine receptor-mediated neuroprotection against Abeta-(1–42) amyloid. J Biol Chem. 2002, 277: 44920-44924.PubMedGoogle Scholar
- Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999, 96: 857-868.PubMedGoogle Scholar
- Cahill CM, Tzivion G, Nasrin N, Ogg S, Dore J, Ruvkun G, Alexander-Bridges M: Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA binding and function via 14-3-3-dependent and 14-3-3-independent pathways. J Biol Chem. 2001, 276: 13402-13410.PubMedGoogle Scholar
- Rena G, Prescott AR, Guo S, Cohen P, Unterman TG: Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting. Biochem J. 2001, 354: 605-612.PubMed CentralPubMedGoogle Scholar
- Zeidler R, Albermann K, Lang S: Nicotine and apoptosis. Apoptosis. 2007, 12: 1927-1943.PubMedGoogle Scholar
- Mai H, May WS, Gao F, Jin Z, Deng X: A functional role for nicotine in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem. 2003, 278: 1886-1891.PubMedGoogle Scholar
- West KA, Brognard J, Clark AS, Linnoila IR, Yang X, Swain SM, Harris C, Belinsky S, Dennis PA: Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J Clin Invest. 2003, 111: 81-90.PubMed CentralPubMedGoogle Scholar
- Jin Z, Gao F, Flagg T, Deng X: Nicotine induces multi-site phosphorylation of Bad in association with suppression of apoptosis. J Biol Chem. 2004, 279: 23837-23844.PubMedGoogle Scholar
- Scheid MP, Schubert KM, Duronio V: Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase. J Biol Chem. 1999, 274: 31108-31113.PubMedGoogle Scholar
- Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997, 91: 231-241.PubMedGoogle Scholar
- Zhou XM, Liu Y, Payne G, Lutz RJ, Chittenden T: Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser155. J Biol Chem. 2000, 275: 25046-25051.PubMedGoogle Scholar
- Fang X, Yu S, Eder A, Mao M, Bast RC Jr, Boyd D, Mills GB: Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene. 1999, 18: 6635-6640.PubMedGoogle Scholar
- Schuller HM: Is cancer triggered by altered signalling of nicotinic acetylcholine receptors?. Nat Rev Cancer. 2009, 9: 195-205.PubMedGoogle Scholar
- Xin M, Deng X: Nicotine inactivation of the proapoptotic function of Bax through phosphorylation. J Biol Chem. 2005, 280: 10781-10789.PubMedGoogle Scholar
- Xin M, Gao F, May WS, Flagg T, Deng X: Protein kinase Czeta abrogates the proapoptotic function of Bax through phosphorylation. J Biol Chem. 2007, 282: 21268-21277.PubMedGoogle Scholar
- Dasgupta P, Kinkade R, Joshi B, Decook C, Haura E, Chellappan S: Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin. Proc Natl Acad Sci USA. 2006, 103: 6332-6337.PubMed CentralPubMedGoogle Scholar
- Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, Kume T, Akaike A: alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta-amyloid-induced neurotoxicity. J Biol Chem. 2001, 276: 13541-13546.PubMedGoogle Scholar
- Berger F, Gage FH, Vijayaraghavan S: Nicotinic receptor-induced apoptotic cell death of hippocampal progenitor cells. J Neurosci. 1998, 18: 6871-6881.PubMedGoogle Scholar
- Guan ZZ, Yu WF, Nordberg A: Dual effects of nicotine on oxidative stress and neuroprotection in PC12 cells. Neurochem Int. 2003, 43: 243-249.PubMedGoogle Scholar
- Hejmadi MV, Dajas-Bailador F, Barns SM, Jones B, Wonnacott S: Neuroprotection by nicotine against hypoxia-induced apoptosis in cortical cultures involves activation of multiple nicotinic acetylcholine receptor subtypes. Mol Cell Neurosci. 2003, 24: 779-786.PubMedGoogle Scholar
- Jonnala RR, Graham JH, Terry AV Jr, Beach JW, Young JA, Buccafusco JJ: Relative levels of cytoprotection produced by analogs of choline and the role of alpha7-nicotinic acetylcholine receptors. Synapse. 2003, 47: 262-269.PubMedGoogle Scholar
- Okuda S, Saito H, Katsuki H: Arachidonic acid: toxic and trophic effects on cultured hippocampal neurons. Neuroscience. 1994, 63: 691-699.PubMedGoogle Scholar
- Serova L, Sabban EL: Involvement of alpha 7 nicotinic acetylcholine receptors in gene expression of dopamine biosynthetic enzymes in rat brain. J Pharmacol Exp Ther. 2002, 303: 896-903.PubMedGoogle Scholar
- Belluardo N, Mudo G, Blum M, Itoh N, Agnati L, Fuxe K: Nicotine-induced FGF-2 mRNA in rat brain is preserved during aging. Neurobiol Aging. 2004, 25: 1333-1342.PubMedGoogle Scholar
- Hsu YN, Edwards SC, Wecker L: Nicotine enhances the cyclic AMP-dependent protein kinase-mediated phosphorylation of alpha4 subunits of neuronal nicotinic receptors. J Neurochem. 1997, 69: 2427-2431.PubMedGoogle Scholar
- Garrido R, Mattson MP, Hennig B, Toborek M: Nicotine protects against arachidonic-acid-induced caspase activation, cytochrome c release and apoptosis of cultured spinal cord neurons. J Neurochem. 2001, 76: 1395-1403.PubMedGoogle Scholar
- Nakayama H, Shioda S, Okuda H, Nakashima T, Nakai Y: Immunocytochemical localization of nicotinic acetylcholine receptor in rat cerebral cortex. Brain Res Mol Brain Res. 1995, 32: 321-328.PubMedGoogle Scholar
- Berg DK, Conroy WG: Nicotinic alpha 7 receptors: synaptic options and downstream signaling in neurons. J Neurobiol. 2002, 53: 512-523.PubMedGoogle Scholar
- Trombino S, Cesario A, Margaritora S, Granone P, Motta G, Falugi C, Russo P: Alpha7-nicotinic acetylcholine receptors affect growth regulation of human mesothelioma cells: role of mitogen-activated protein kinase pathway. Cancer Res. 2004, 64: 135-145.PubMedGoogle Scholar
- Schuller HM, Tithof PK, Williams M, Plummer H: The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a beta-adrenergic agonist and stimulates DNA synthesis in lung adenocarcinoma via beta-adrenergic receptor-mediated release of arachidonic acid. Cancer Res. 1999, 59: 4510-4515.PubMedGoogle Scholar
- Gimonet D, Grailhe R, Coninx P, Antonicelli F, Haye B, Liautaud-Roger F: Functional role of nicotinic acetylcholine receptors in apoptosis in HL-60 cell line. Eur J Pharmacol. 2003, 482: 25-29.PubMedGoogle Scholar
- Heusch WL, Maneckjee R: Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells. Carcinogenesis. 1998, 19: 551-556.PubMedGoogle Scholar
- Finkbeiner S: CREB couples neurotrophin signals to survival messages. Neuron. 2000, 25: 11-14.PubMedGoogle Scholar
- Mazzucchelli C, Brambilla R: Ras-related and MAPK signalling in neuronal plasticity and memory formation. Cell Mol Life Sci. 2000, 57: 604-611.PubMedGoogle Scholar
- Zhu Y, Culmsee C, Klumpp S, Krieglstein J: Neuroprotection by transforming growth factor-beta1 involves activation of nuclear factor-kappaB through phosphatidylinositol-3-OH kinase/Akt and mitogen-activated protein kinase-extracellular-signal regulated kinase1,2 signaling pathways. Neuroscience. 2004, 123: 897-906.PubMedGoogle Scholar
- Mattson MP, Culmsee C, Yu Z, Camandola S: Roles of nuclear factor kappaB in neuronal survival and plasticity. J Neurochem. 2000, 74: 443-456.PubMedGoogle Scholar
- Mayr B, Montminy M: Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol. 2001, 2: 599-609.PubMedGoogle Scholar
- Zha XM, Bishop JF, Hansen MR, Victoria L, Abbas PJ, Mouradian MM, Green SH: BDNF synthesis in spiral ganglion neurons is constitutive and CREB-dependent. Hear Res. 2001, 156: 53-68.PubMedGoogle Scholar
- Wasylyk B, Hagman J, Gutierrez-Hartmann A: Ets transcription factors: nuclear effectors of the Ras-MAP-kinase signaling pathway. Trends Biochem Sci. 1998, 23: 213-216.PubMedGoogle Scholar
- Shibata F, Baird A, Florkiewicz RZ: Functional characterization of the human basic fibroblast growth factor gene promoter. Growth Factors. 1991, 4: 277-287.PubMedGoogle Scholar
- Schweppe RE, Frazer-Abel AA, Gutierrez-Hartmann A, Bradford AP: Functional components of fibroblast growth factor (FGF) signal transduction in pituitary cells. J Biol Chem. 1997, 272: 30852-30859.PubMedGoogle Scholar
- Zhou C, Wen ZX, Shi DM, Xie ZP: Muscarinic acetylcholine receptors involved in the regulation of neural stem cell proliferation and differentiation in vitro. Cell Biol Int. 2004, 28: 63-67.PubMedGoogle Scholar
- Jang YY, Sharkis SJ: Stem cell plasticity: a rare cell, not a rare event. Stem Cell Rev. 2005, 1: 45-51.PubMedGoogle Scholar
- Chang L, Karin M: Mammalian MAP kinase signalling cascades. Nature. 2001, 410: 37-40.PubMedGoogle Scholar
- Resende RR, Faria M, Ulrich H: The contribution of nitric oxide and carbon monoxide to neuronal function and development. Central Nervous System Agents in Medicinal Chemistry. 2007, 7: 85-96.Google Scholar
- Felder CC: Muscarinic acetylcholine receptors: signal transduction through multiple effectors. Faseb J. 1995, 9: 619-625.PubMedGoogle Scholar
- Iwasaki H, Shichiri M, Marumo F, Hirata Y: Adrenomedullin stimulates proline-rich tyrosine kinase 2 in vascular smooth muscle cells. Endocrinology. 2001, 142: 564-572.PubMedGoogle Scholar
- Della Rocca GJ, Mukhin YV, Garnovskaya MN, Daaka Y, Clark GJ, Luttrell LM, Lefkowitz RJ, Raymond JR: Serotonin 5-HT1A receptor-mediated Erk activation requires calcium/calmodulin-dependent receptor endocytosis. J Biol Chem. 1999, 274: 4749-4753.PubMedGoogle Scholar
- Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D, Rapp UR: Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature. 1993, 364: 249-252.PubMedGoogle Scholar
- Shah BH, Catt KJ: Calcium-independent activation of extracellularly regulated kinases 1 and 2 by angiotensin II in hepatic C9 cells: roles of protein kinase Cdelta, Src/proline-rich tyrosine kinase 2, and epidermal growth receptor trans-activation. Mol Pharmacol. 2002, 61: 343-351.PubMedGoogle Scholar
- Liebmann C, Bohmer FD: Signal transduction pathways of G protein-coupled receptors and their cross-talk with receptor tyrosine kinases: lessons from bradykinin signaling. Curr Med Chem. 2000, 7: 911-943.PubMedGoogle Scholar
- Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH: Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001, 22: 153-183.PubMedGoogle Scholar
- Wilkinson MG, Millar JB: Control of the eukaryotic cell cycle by MAP kinase signaling pathways. Faseb J. 2000, 14: 2147-2157.PubMedGoogle Scholar
- Li BS, Ma W, Zhang L, Barker JL, Stenger DA, Pant HC: Activation of phosphatidylinositol-3 kinase (PI-3K) and extracellular regulated kinases (Erk1/2) is involved in muscarinic receptor-mediated DNA synthesis in neural progenitor cells. J Neurosci. 2001, 21: 1569-1579.PubMedGoogle Scholar
- Allen LF, Lefkowitz RJ, Caron MG, Cotecchia S: G-protein-coupled receptor genes as protooncogenes: constitutively activating mutation of the alpha 1B-adrenergic receptor enhances mitogenesis and tumorigenicity. Proc Natl Acad Sci USA. 1991, 88: 11354-11358.PubMed CentralPubMedGoogle Scholar
- Gutkind JS, Novotny EA, Brann MR, Robbins KC: Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes. Proc Natl Acad Sci USA. 1991, 88: 4703-4707.PubMed CentralPubMedGoogle Scholar
- Couty JP, Gershengorn MC: Insights into the viral G protein-coupled receptor encoded by human herpesvirus type 8 (HHV-8). Biol Cell. 2004, 96: 349-354.PubMedGoogle Scholar
- Vischer HF, Leurs R, Smit MJ: HCMV-encoded G-protein-coupled receptors as constitutively active modulators of cellular signaling networks. Trends Pharmacol Sci. 2006, 27: 56-63.PubMedGoogle Scholar
- Ballif BA, Blenis J: Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals. Cell Growth Differ. 2001, 12: 397-408.PubMedGoogle Scholar
- Mercer SE, Friedman E: Mirk/Dyrk1B: a multifunctional dual-specificity kinase involved in growth arrest, differentiation, and cell survival. Cell Biochem Biophys. 2006, 45: 303-315.PubMedGoogle Scholar
- Dhanasekaran DN, Kashef K, Lee CM, Xu H, Reddy EP: Scaffold proteins of MAP-kinase modules. Oncogene. 2007, 26: 3185-3202.PubMedGoogle Scholar
- Pronk GJ, Bos JL: The role of p21ras in receptor tyrosine kinase signalling. Biochim Biophys Acta. 1994, 1198: 131-147.PubMedGoogle Scholar
- van Corven EJ, Hordijk PL, Medema RH, Bos JL, Moolenaar WH: Pertussis toxin-sensitive activation of p21ras by G protein-coupled receptor agonists in fibroblasts. Proc Natl Acad Sci USA. 1993, 90: 1257-1261.PubMed CentralPubMedGoogle Scholar
- Koch WJ, Hawes BE, Allen LF, Lefkowitz RJ: Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras. Proc Natl Acad Sci USA. 1994, 91: 12706-12710.PubMed CentralPubMedGoogle Scholar
- Daub H, Weiss FU, Wallasch C, Ullrich A: Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature. 1996, 379: 557-560.PubMedGoogle Scholar
- Eguchi S, Numaguchi K, Iwasaki H, Matsumoto T, Yamakawa T, Utsunomiya H, Motley ED, Kawakatsu H, Owada KM, Hirata Y, et al.: Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. J Biol Chem. 1998, 273: 8890-8896.PubMedGoogle Scholar
- Hawes BE, van Biesen T, Koch WJ, Luttrell LM, Lefkowitz RJ: Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation. J Biol Chem. 1995, 270: 17148-17153.PubMedGoogle Scholar
- Blaukat A, Barac A, Cross MJ, Offermanns S, Dikic I: G protein-coupled receptor-mediated mitogen-activated protein kinase activation through cooperation of Galpha(q) and Galpha(i) signals. Mol Cell Biol. 2000, 20: 6837-6848.PubMed CentralPubMedGoogle Scholar
- Winitz S, Russell M, Qian NX, Gardner A, Dwyer L, Johnson GL: Involvement of Ras and Raf in the Gi-coupled acetylcholine muscarinic m2 receptor activation of mitogen-activated protein (MAP) kinase kinase and MAP kinase. J Biol Chem. 1993, 268: 19196-19199.PubMedGoogle Scholar
- Russell M, Winitz S, Johnson GL: Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity. Mol Cell Biol. 1994, 14: 2343-2351.PubMed CentralPubMedGoogle Scholar
- Guizzetti M, Costa LG: Activation of phosphatidylinositol 3 kinase by muscarinic receptors in astrocytoma cells. Neuroreport. 2001, 12: 1639-1642.PubMedGoogle Scholar
- Yeo A, Samways DS, Fowler CE, Gunn-Moore F, Henderson G: Coincident signalling between the Gi/Go-coupled delta-opioid receptor and the Gq-coupled m3 muscarinic receptor at the level of intracellular free calcium in SH-SY5Y cells. J Neurochem. 2001, 76: 1688-1700.PubMedGoogle Scholar
- Berkeley JL, Levey AI: Cell-specific extracellular signal-regulated kinase activation by multiple G protein-coupled receptor families in hippocampus. Mol Pharmacol. 2003, 63: 128-135.PubMedGoogle Scholar
- Chan AS, Yeung WW, Wong YH: Integration of G protein signals by extracellular signal-regulated protein kinases in SK-N-MC neuroepithelioma cells. J Neurochem. 2005, 94: 1457-1470.PubMedGoogle Scholar
- Slack BE: The m3 muscarinic acetylcholine receptor is coupled to mitogen-activated protein kinase via protein kinase C and epidermal growth factor receptor kinase. Biochem J. 2000, 348 (Pt 2): 381-387.PubMed CentralPubMedGoogle Scholar
- Rosenblum K, Futter M, Jones M, Hulme EC, Bliss TV: ERKI/II regulation by the muscarinic acetylcholine receptors in neurons. J Neurosci. 2000, 20: 977-985.PubMedGoogle Scholar
- Montiel M, Pavia J, Marsigliante S, Jimenez E: Activation of muscarinic acetylcholine receptors induces Ca(2+) mobilization in FRT cells. Cell Signal. 2001, 13: 207-212.PubMedGoogle Scholar
- Montiel M, Quesada J, Jimenez E: Activation of second messenger-dependent protein kinases induces muscarinic acetylcholine receptor desensitization in rat thyroid epithelial cells. Mol Cell Endocrinol. 2004, 223: 35-41.PubMedGoogle Scholar
- Fan WT, Koch CA, de Hoog CL, Fam NP, Moran MF: The exchange factor Ras-GRF2 activates Ras-dependent and Rac-dependent mitogen-activated protein kinase pathways. Curr Biol. 1998, 8: 935-938.PubMedGoogle Scholar
- Ebinu JO, Stang SL, Teixeira C, Bottorff DA, Hooton J, Blumberg PM, Barry M, Bleakley RC, Ostergaard HL, Stone JC: RasGRP links T-cell receptor signaling to Ras. Blood. 2000, 95: 3199-3203.PubMedGoogle Scholar
- Sanjuan MA, Pradet-Balade B, Jones DR, Martinez AC, Stone JC, Garcia-Sanz JA, Merida I: T cell activation in vivo targets diacylglycerol kinase alpha to the membrane: a novel mechanism for Ras attenuation. J Immunol. 2003, 170: 2877-2883.PubMedGoogle Scholar
- Hamilton SE, Nathanson NM: The M1 receptor is required for muscarinic activation of mitogen-activated protein (MAP) kinase in murine cerebral cortical neurons. J Biol Chem. 2001, 276: 15850-15853.PubMedGoogle Scholar
- Keely SJ, Calandrella SO, Barrett KE: Carbachol-stimulated transactivation of epidermal growth factor receptor and mitogen-activated protein kinase in T(84) cells is mediated by intracellular ca(2+), PYK-2, and p60(src). J Biol Chem. 2000, 275: 12619-12625.PubMedGoogle Scholar
- Derkinderen P, Siciliano J, Toutant M, Girault JA: Differential regulation of FAK+ and PYK2/Cakbeta, two related tyrosine kinases, in rat hippocampal slices: effects of LPA, carbachol, depolarization and hyperosmolarity. Eur J Neurosci. 1998, 10: 1667-1675.PubMedGoogle Scholar
- Li X, Lee JW, Graves LM, Earp HS: Angiotensin II stimulates ERK via two pathways in epithelial cells: protein kinase C suppresses a G-protein coupled receptor-EGF receptor transactivation pathway. Embo J. 1998, 17: 2574-2583.PubMed CentralPubMedGoogle Scholar
- Jope RS, Song L, Grimes CA, Zhang L: Oxidative stress oppositely modulates protein tyrosine phosphorylation stimulated by muscarinic G protein-coupled and epidermal growth factor receptors. J Neurosci Res. 1999, 55: 329-340.PubMedGoogle Scholar
- Shah BH, Olivares-Reyes JA, Catt KJ: The protein kinase C inhibitor Go6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)py rrolo(3,4-c)-carbazole] potentiates agonist-induced mitogen-activated protein kinase activation through tyrosine phosphorylation of the epidermal growth factor receptor. Mol Pharmacol. 2005, 67: 184-194.PubMedGoogle Scholar
- Crespo P, Xu N, Daniotti JL, Troppmair J, Rapp UR, Gutkind JS: Signaling through transforming G protein-coupled receptors in NIH 3T3 cells involves c-Raf activation. J Biol Chem. 1994, 269: 21103-21109.PubMedGoogle Scholar
- Hawkins BT, Egleton RD, Davis TP: Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors. Am J Physiol Heart Circ Physiol. 2005, 289: H212-219.PubMedGoogle Scholar
- Abbruscato TJ, Lopez SP, Roder K, Paulson JR: Regulation of blood-brain barrier Na,K,2Cl-cotransporter through phosphorylation during in vitro stroke conditions and nicotine exposure. J Pharmacol Exp Ther. 2004, 310: 459-468.PubMedGoogle Scholar
- Howard MJ, Gershon MD, Margiotta JF: Expression of nicotinic acetylcholine receptors and subunit mRNA transcripts in cultures of neural crest cells. Dev Biol. 1995, 170: 479-495.PubMedGoogle Scholar
- De Simone R, Ajmone-Cat MA, Carnevale D, Minghetti L: Activation of alpha7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures. J Neuroinflammation. 2005, 2: 4-PubMed CentralPubMedGoogle Scholar
- Sharma G, Vijayaraghavan S: Nicotinic receptor signaling in nonexcitable cells. J Neurobiol. 2002, 53: 524-534.PubMedGoogle Scholar
- Conklin BS, Zhao W, Zhong DS, Chen C: Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells. Am J Pathol. 2002, 160: 413-418.PubMed CentralPubMedGoogle Scholar
- Xu L, Deng X: Protein kinase Ciota promotes nicotine-induced migration and invasion of cancer cells via phosphorylation of micro- and m-calpains. J Biol Chem. 2006, 281: 4457-4466.PubMedGoogle Scholar
- Shin VY, Wu WK, Chu KM, Wong HP, Lam EK, Tai EK, Koo MW, Cho CH: Nicotine induces cyclooxygenase-2 and vascular endothelial growth factor receptor-2 in association with tumor-associated invasion and angiogenesis in gastric cancer. Mol Cancer Res. 2005, 3: 607-615.PubMedGoogle Scholar
- Chu M, Guo J, Chen CY: Long-term exposure to nicotine, via ras pathway, induces cyclin D1 to stimulate G1 cell cycle transition. J Biol Chem. 2005, 280: 6369-6379.PubMedGoogle Scholar
- Dasgupta P, Rastogi S, Pillai S, Ordonez-Ercan D, Morris M, Haura E, Chellappan S: Nicotine induces cell proliferation by beta-arrestin-mediated activation of Src and Rb-Raf-1 pathways. J Clin Invest. 2006, 116: 2208-2217.PubMed CentralPubMedGoogle Scholar
- Leanza G, Muir J, Nilsson OG, Wiley RG, Dunnett SB, Bjorklund A: Selective immunolesioning of the basal forebrain cholinergic system disrupts short-term memory in rats. Eur J Neurosci. 1996, 8: 1535-1544.PubMedGoogle Scholar
- Xie DP, Chen LB, Liu CY, Zhang CL, Liu KJ, Wang PS: Arecoline excites the colonic smooth muscle motility via M3 receptor in rabbits. Chin J Physiol. 2004, 47: 89-94.PubMedGoogle Scholar
- Margiotta JF, Berg DK, Dionne VE: The properties and regulation of functional acetylcholine receptors on chick ciliary ganglion neurons. J Neurosci. 1987, 7: 3612-3622.PubMedGoogle Scholar
- Arias HR: Agonist self-inhibitory binding site of the nicotinic acetylcholine receptor. J Neurosci Res. 1996, 44: 97-105.PubMedGoogle Scholar
- Sokolova E, Matteoni C, Nistri A: Desensitization of neuronal nicotinic receptors of human neuroblastoma SH-SY5Y cells during short or long exposure to nicotine. Br J Pharmacol. 2005, 146: 1087-1095.PubMed CentralPubMedGoogle Scholar
- Mulle C, Benoit P, Pinset C, Roa M, Changeux JP: Calcitonin gene-related peptide enhances the rate of desensitization of the nicotinic acetylcholine receptor in cultured mouse muscle cells. Proc Natl Acad Sci USA. 1988, 85: 5728-5732.PubMed CentralPubMedGoogle Scholar
- Miles K, Greengard P, Huganir RL: Calcitonin gene-related peptide regulates phosphorylation of the nicotinic acetylcholine receptor in rat myotubes. Neuron. 1989, 2: 1517-1524.PubMedGoogle Scholar
- Giniatullin R, Di Angelantonio S, Marchetti C, Sokolova E, Khiroug L, Nistri A: Calcitonin gene-related peptide rapidly downregulates nicotinic receptor function and slowly raises intracellular Ca2+ in rat chromaffin cells in vitro. J Neurosci. 1999, 19: 2945-2953.PubMedGoogle Scholar
- Di Angelantonio S, Costa V, Carloni P, Messori L, Nistri A: A novel class of peptides with facilitating action on neuronal nicotinic receptors of rat chromaffin cells in vitro: functional and molecular dynamics studies. Mol Pharmacol. 2002, 61: 43-54.PubMedGoogle Scholar
- Leonard S, Gault J, Hopkins J, Logel J, Vianzon R, Short M, Drebing C, Berger R, Venn D, Sirota P, et al.: Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry. 2002, 59: 1085-1096.PubMedGoogle Scholar
- D'Ascenzo M, Piacentini R, Casalbore P, Budoni M, Pallini R, Azzena GB, Grassi C: Role of L-type Ca2+ channels in neural stem/progenitor cell differentiation. Eur J Neurosci. 2006, 23: 935-944.PubMedGoogle Scholar
- Resende RR, da Costa JL, Kihara AH, Adhikari A, Lorencon E: Intracellular Ca(2+) Regulation During Neuronal Differentiation of Murine Embryonal Carcinoma and Mesenchymal Stem Cells. Stem Cells Dev. 2008,Google Scholar
- Nagasawa K, Tarui T, Yoshida S, Sekiguchi F, Matsunami M, Ohi A, Fukami K, Ichida S, Nishikawa H, Kawabata A: Hydrogen sulfide evokes neurite outgrowth and expression of high-voltage-activated Ca2+ currents in NG108-15 cells: involvement of T-type Ca2+ channels. J Neurochem. 2009, 108: 676-684.PubMedGoogle Scholar
- Hirooka K, Bertolesi GE, Kelly ME, Denovan-Wright EM, Sun X, Hamid J, Zamponi GW, Juhasz AE, Haynes LW, Barnes S: T-Type calcium channel alpha1G and alpha1H subunits in human retinoblastoma cells and their loss after differentiation. J Neurophysiol. 2002, 88: 196-205.PubMedGoogle Scholar
- Bertolesi GE, Shi C, Elbaum L, Jollimore C, Rozenberg G, Barnes S, Kelly ME: The Ca(2+) channel antagonists mibefradil and pimozide inhibit cell growth via different cytotoxic mechanisms. Mol Pharmacol. 2002, 62: 210-219.PubMedGoogle Scholar
- Mason RP, Leeds PR, Jacob RF, Hough CJ, Zhang KG, Mason PE, Chuang DM: Inhibition of excessive neuronal apoptosis by the calcium antagonist amlodipine and antioxidants in cerebellar granule cells. J Neurochem. 1999, 72: 1448-1456.PubMedGoogle Scholar
- Yamagata K, Ichinose S, Tagami M: Amlodipine and carvedilol prevent cytotoxicity in cortical neurons isolated from stroke-prone spontaneously hypertensive rats. Hypertens Res. 2004, 27: 271-282.PubMedGoogle Scholar
- Brinton RD, Wang JM: Preclinical analyses of the therapeutic potential of allopregnanolone to promote neurogenesis in vitro and in vivo in transgenic mouse model of Alzheimer's disease. Curr Alzheimer Res. 2006, 3: 11-17.PubMedGoogle Scholar
- Liu JW, Tian SJ, de Barry J, Luu B: Panaxadiol glycosides that induce neuronal differentiation in neurosphere stem cells. J Nat Prod. 2007, 70: 1329-1334.PubMedGoogle Scholar
- Yoshida J, Ishibashi T, Nishio M: Antiproliferative effect of Ca2+ channel blockers on human epidermoid carcinoma A431 cells. Eur J Pharmacol. 2003, 472: 23-31.PubMedGoogle Scholar
- Arredondo J, Chernyavsky AI, Grando SA: SLURP-1 and -2 in normal, immortalized and malignant oral keratinocytes. Life Sci. 2007, 80: 2243-2247.PubMed CentralPubMedGoogle Scholar
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