Signalling 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. Beta 1- and beta 2- and possibly beta 3-adrenoceptors (beta-AR) are found in the hearts of humans and common laboratory animals such as rats and guinea-pigs. In rats and guinea-pigs chronic stimulation of cardiac 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 beta 2-AR. 3. Desensitization is also associated with phosphorylation of beta-AR by beta-AR kinase (beta-ARK) and uncoupling of receptors from the signalling pathway. Beta-ARK but not beta-arrestin activity and mRNA are markedly increased in heart failure. 4. Chronic beta-AR stimulation 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.


BACKGROUND
beta-ARK - beta-adrenoceptor kinase AR - adrenoceptor G-protein - GTP binding protein
Summers
R J
RJ
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
McMartin
L R
LR
Kompa
A
A
Gu
X
X
Molenaar
P
P
D000818:Animals; D002303:Cardiac Output, Low / Q000378:metabolism / Q000503:physiopathology*; D019204:GTP-Binding Proteins / Q000502:physiology; D006168:Guinea Pigs; D009206:Myocardium / Q000737:chemistry; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins