Inhibitory G-proteins and their role in desensitization of the adenylyl cyclase pathway in heart failure.
Heart failure is accompanied by stereotypic alterations in cardiac gene expression. These changes are most likely secondary in the pathogenesis and can be viewed as protective, e.g. as energy-saving mechanisms, but at the same time, they aggravate contractile dysfunction and the deficit of failing cardiac myocytes to respond to altered hemodynamic needs. One of the best-studied, paradigmatic examples of this dichotomy is heterologous desensitization of the cardiac adenylyl cyclase (AC) signaling pathway. It protects against detrimental consequences of the excessive adrenergic drive, but it also blunts the most powerful inotropic support of the heart. Desensitization is associated with downregulation of beta-adrenergic receptors, increased beta-adrenoceptor kinases and increased inhibitory G protein alpha-subunits, G(alphai). Whereas a causative role of the former is generally accepted, the role of the increase in G(alphai) has remained controversial for many years. The present article summarizes early and novel findings that, in the view of the authors, provide solid evidence for G(alphai) to play an important role in the adaptation of cardiac AC to various pathophysiological conditions.
El-Armouche
Ali
A
Institut für Experimentelle und Klinische Pharmakologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Zolk
Oliver
O
Rau
Thomas
T
Eschenhagen
Thomas
T
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000242:Cyclic AMP / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000319:Adrenergic beta-Antagonists; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases