SIGNALING PATHWAYS IN CARDIAC-FAILURE

1. Cardiac failure in humans and in animal models is associated with a marked desensitization of the catecholamine signalling pathway. 2. be ta(1)- and beta(2)- and possibly beta(3)-adrenoceptors (beta-AR) are f ound in the hearts of humans and common laboratory animals such as rat s and guinea-pigs, In rats and guinea-pigs chronic stimulation of card iac beta-AR leads to a rapid loss of beta(2)-AR whereas heart failure in humans is associated with a loss of beta(1)-AR or beta(1)-AR and be ta(2)-AR. 3. Desensitization is also associated with phosphorylation o f beta-AR by beta-AR kinase (beta-ARK) and uncoupling of receptors fro m the signalling pathway. beta-ARK but not beta-arrestin activity and mRNA are markedly Increased in heart failure. 4. Chronic beta-AR stimu lation and heart failure are associated with increases in Gi alpha but little if any change in Gs alpha. 5. The roles of beta gamma subunits of G-proteins, adenylate cyclase subtypes and cAMP dependent protein kinase A in heart failure are unclear at present. Abbreviations: beta- ARK - beta-adrenoceptor kinase AR - adrenoceptor G-protein - GTP bindi ng protein.