Molecular regulation of PLCβ signaling

Phospholipase C (PLC) enzymes convert the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) into inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 and DAG regulate numerous downstream pathways, eliciting diverse and profound cellular changes and physiological responses. In the six PLC subfamilies in higher eukaryotes, PLCβ is intensively studied due to its prominent role in regulating crucial cellular events underlying many processes including cardiovascular and neuronal signaling, and associated pathological conditions. In addition to GαqGTP, Gβγ generated upon G protein heterotrimer dissociation also regulates PLCβ activity. Here, we not only review how Gβγ directly activates PLCβ, and also extensively modulates Gαq-mediated PLCβ activity, but also provide a structure-function overview of PLC family members. Given that Gαq and PLCβ are oncogenes, and Gβγ shows unique cell-tissue-organ specific expression profiles, Gγ subtype-dependent signaling efficacies, and distinct subcellular activities, this review proposes that Gβγ is a major regulator of Gαq-dependent and independent PLCβ signaling.