title: Beta-adrenergic signal transduction in the failing and hypertrophied myocardium.
abstract: A strong sympathetic activation has been observed in heart failure and is the cause of beta-adrenergic desensitization in this condition. On the receptor level there is downregulation of beta1-adrenergic receptors and uncoupling of beta2-adrenoceptors. The latter mechanism has been related to an increased activity and gene expression of beta-adrenoceptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. beta3-Adrenoceptors mediate negative inotropic effects, but alterations in these receptors are not known. In addition, an increase in inhibitory G protein alpha subunits (Gi alpha) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G protein alpha and betagamma subunits, have been observed to be unchanged. Recent evidence shows that increases in Gi alpha also depress adenylyl cyclase in compensated cardiac hypertrophy both in monogenic and polygenic and in secondary hypertension. These increases of Gi alpha can suppress adenylyl cyclase in the absence of beta-adrenergic receptor downregulation. Since cardiac hypertrophy in pressure overload is a strong predictor of cardiac failure, these observations indicate that adenylyl cyclase desensitization by Gi alpha may be a pathophysiologically relevant mechanism contributing to the progression from compensated cardiac hypertrophy to heart failure.
authors.affiliation: Klinik III für Innere Medizin, Universität Köln, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Böhm
authors.forename: M
authors.initials: M
authors.lastname: Flesch
authors.forename: P
authors.initials: P
authors.lastname: Schnabel
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D011943:Receptors, Adrenergic, beta