Fig. 5
From: GPR91: expanding the frontiers of Krebs cycle intermediates
Succinate causes cardiomyocyte hypertrophy via GPR91 activation. Succinate accumulation in the blood stream reaches the cardiac muscle cells to activate GPR91, consequently triggering at least two separate intracellular signaling pathways. In one pathway, GPR91 stimulates MEK1/2 that phosphorylates ERK1/2. Phosphorylated ERK1/2 is translocated to the nucleus, where it activates transcription of hypertrophic genes. In an alternative pathway, GPR91 activates PLC, which produces inositol-3-phosphate and diacylglycerol. IP3 binds to its receptor, releasing Ca2+ from the sarcoplasmic reticulum to the cytosol. Ca2+ activates CaMKIIδ that moves to the nucleus and phosphorylates HDAC5, which is released from transcription factor MEF2 allowing the transcription of hypertrophic genes