ENDOTHELIN-1-DEPENDENT SIGNALING PATHWAYS IN THE MYOCARDIUM

Endothelin-1 (ET-1) is a locally acting vasoactive peptide that also h as profound effects on the contractile properties and growth of the ca rdiac myocyte. Binding of ET-1 to its transmembrane heptahelical recep tors activates G proteins of the G(q) and G(i) classes. Activation of G(q) stimulates hydrolysis of phosphatidylinositol-4, 5-bisphosphate, and the diacylglycerol thus formed stimulates protein kinase C. Subseq uently, the protein kinase Raf is activated and this leads to activati on of the extracellular signal-regulated protein kinase (ERK) subfamil y of mitogen-activated protein kinases. Activation of G(i) counteracts beta-adrenoceptor-mediated increases in cAMP concentrations. We have attempted to rationalize the established physiological consequences of ET-1 agonism in the cardiac myocyte (that is, on contraction and grow th) in terms of activation of these signaling pathways.