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Fig. 9 | Cell Communication and Signaling

Fig. 9

From: cAMP- and cGMP-elevating agents inhibit GPIbα-mediated aggregation but not GPIbα-stimulated Syk activation in human platelets

Fig. 9

cAMP/PKA and cGMP/PKG pathways cause dichotomous regulation of GPIbα-mediated Syk stimulation and activation of human platelets. Selective binding of the snake venom toxin echicetin as multimeric complex (echicetin beads, EB) to the extracellular domain of GPIbα leads to GPIbα crosslinking and initiates a signaling cascade starting from activation of src family kinases (SFK). This GPIbα activation results in tyrosine phosphorylation of ITAM-containing FcRγ-chains and SFK-dependent phosphorylation and recruitment of the spleen tyrosine kinase (Syk), via its SH2 domains to tyrosine phosphorylated ITAMs produce full Syk activation. Syk-dependent phosphorylation and activation of the adaptor protein (LAT), phospholipase Cγ2 and others lead to increased levels of InsP3 (IP3; measured here by its metabolite InsP1) and DAG, which are responsible for Ca2+-release and PKC activation (dotted black arrows). Additionally, Syk mediates indirectly the phosphorylation of Akt, one of Syk downstream effectors (dotted black arrow). Altogether, this leads to integrin activation, granule release and TxA2 synthesis and subsequent platelet aggregation. The major platelet inhibitory pathways represented by cAMP/PKA and cGMP/PKG strongly enhance EB-induced Syk phosphorylation/activation (dotted green arrows) and enhance Syk-mediated tyrosine phosphorylation of LAT and PLCγ2 whereas InsP3 increase and Ca2+-release are partially inhibited, Akt phosphorylation is strongly inhibited (dotted red bars). The net effect of this crosstalk between platelet activation by EB and inhibition by cAMP/PKA and cGMP/PKG is marked with up or down black arrows (arrow number reflects the intensity of the effect). Syk and its direct substrates PLCγ2 and LAT are strongly activated (three arrows direction up), InsP3 and its subsequent Ca2+-release are partially inhibited (one arrow down). The phosphorylation of Akt is strongly inhibited by PKA and PKG-elevating agents, similar to the overall aggregation (three arrows direction down)

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