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Activation of PKC through GPCR

Protein Kinase C (PKC) refers to a multigene family of kinases classified as conventional: (PKCalpha; PKCbeta1 and PKCbeta2 (splice variants); and PKCgamma; novel: PKCdelta; PKCepsilon; PKCeta; PKCmu; PKCnu; and PKCtheta; and atypical: PKCiota/lamda and PKCzeta isoforms. The conventional PKC isoforms are activated by calcium (Ca²⁺) and sn-1,2-diacylglycerol (DAG), whereas the novel PKC isoforms are activated by DAG, but not calcium. Both Ca²⁺ and DAG are signaled by the actions of phospholipaseCbeta (PLCβ). PLCβ is activated by the Gαq (Galphaq) subunit of trimeric G-proteins linked to G-protein coupled receptors (GPCRs). GPCRs provide a wide range of specificity for agonist stimulation of conventional and novel PKC mediated cell signaling.

Activated PLCb or PLCg cleaves the inositol substrate phosphatidyl-inositol 4,5 bisphosphate (PIP2) to yield diacylglycerol and inositol 1,4,5-trisphosphate (IP3). DAG is a direct activator of conventional and novel PKCs. Calcium is released from the endoplasmic reticulum (ER) by IP3 and helps localize conventional PKCs to the cell membrane. PKC mediates CPI phosphorylation, which inhibits myosin phosphatase. The accumulation of phosphorylated myosin supports platelet contraction and secretion. The MEK kinase, Raf1 can be phosphorylated by conventional and novel PKC isotypes alpha and eta, but not PKCzeta. Activation of Raf1 leads to activation of ERK1/2 regulated genes. Various PKCs regulate cell survival through the release of NFkBs