Succinate induces calcium mobilization in an adenylyl cyclase (AC) and protein kinase A (PKA)-dependent manner. Succinate receptor 1 (SUCNR1) engagement activates phospholipase C (PLC), resulting in the cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). These second messengers induce calcium mobilization and PKC activation, respectively, and subsequent nitric oxide (NO) and prostaglandin E2 (PGE2) production as well as p38 activation. PKC-dependent phosphorylation of extracellular signal-related kinases ERK1/2 can also drive PG production. SUCNR1 signaling might act in synergy with several inflammatory signaling cascades. PKA is known to phosphorylate and activate the p65 subunit of nuclear factor κB (NF-κB) and cAMP response element-binding protein (CREB). Furthermore, NF-κB, activating protein (AP)-1, nuclear factor of activated T cells (NFAT), and ETS domain-containing protein (Elk-1) are all downstream targets of PKC and MAPKs.

Succinate Signalling During Inflammation References