FUNCTIONAL COUPLING BETWEEN ENDOTHELIN RECEPTORS AND MULTIPLE G-PROTEINS IN RAT-HEART MYOCYTES

Binding data point to the coexistence of three endothelin receptors (E T-R) in rat heart myocytes. Induction of phosphoinositide hydrolysis i n this preparation by endothelins (ET-1 and ET-3) or sarafotoxins (SRT X-b and SRTX-c) was demonstrated by measurement of labeled inositol ph osphate generation. Pertussis toxin (PT) enhanced the induction of pho sphoinositide hydrolysis by all four peptides. The process seems to be mediated by at least two heterotrimeric G-proteins, the one sensitive and the other insensitive to PT. Measurement of GTPase activity induc ed in rat myocytes clearly indicates for the first time the direct fun ctional coupling between ET-R and a G-protein. These GTPase activity e xperiments provide evidence that phosphoinositide hydrolysis is stimul ated via functional coupling between the endothelin receptor of the ET (A)-R subtype and a PT-insensitive G-protein, Gq/11. The involvement o f PT-sensitive G-proteins, i.e. Gi-like and/or Go-like proteins, in th e signal transduction pathways of ETs and SRTXs is discussed.