CYCLIC CMP FORMATION IN RAT CEREBELLAR SLICES IS STIMULATED BY ENDOTHELINS VIA NITRIC-OXIDE FORMATION AND BY SARAFOTOXINS VIA FORMATION OF CARBON-MONOXIDE

Involvement of a cyclic GMP pathway in signal transduction stimulated by endothelins (ETs) and sarafotoxins (SRTXs) was explored using rat c erebellar slices. These peptides activated the same receptor binding s ites (ET-1 and SRTX-b at the picomolar sites; ET-3 and SRTX-c at the n anomolar sites) to produce cyclic GMP, but their signaling pathways di ffered. The endothelins (ET-1 and ET-3) were found to signal via nitri c oxide formation and to involve pertussis toxin-sensitive G-protein(s ), The SRTXs (b and c), while also stimulating cyclic GMP production, did so via a pathway which is not L-arginine-dependent, i.e., carbon m onoxide formation, and did not involve pertussis-toxin-sensitive G-pro tein(s). This is the first demonstration that the signaling pathways o f endothelins and sarafotoxins may differ, even though they share the same binding sites.