SUPPRESSION OF G(I-ALPHA-2) ENHANCES PHOSPHOLIPASE-C SIGNALING

G-proteins mediate transmembrane signalling from a populous group of cell-surface receptors to a smaller group of effectors that includes adenylate cyclase, various ion channels and phospholipase C. Stem cells (F9 teratocarcinoma) or rat osteosarcoma 17/2.8 cells in which G(i alpha 2) expression is abolished by antisense RNA display markedly elevated basal inositol 1,4,5-trisphosphate accumulation and a potentiated phospholipase C response to stimulatory hormones. Expression of the Q205L mutant of G(i alpha 2), which is constitutively active, was found to block persistently hormonally stimulated phospholipase C activity, implicating G(i alpha 2) as an inhibitory regulator of phospholipase C signalling. Analysis using G(i alpha 2)-deficient adipocytes of transgenic mice provided further evidence for a role for G(i alpha 2) in phospholipase C regulation, demonstrating in vivo that loss of G(i alpha 2) elevates basal, and markedly potentiates hormonally stimulated, phospholipase C activity. This report demonstrates for the first time that a single G-protein, G(i2), can regulate two distinct signalling pathways, i.e. adenylate cyclase and phospholipase C.