beta(2)-Adrenergic receptor signaling complexes in cardiomyocyte caveolae/lipid rafts.
The traditional notion that catecholamine actions are mediated by the predominant beta(1)-adrenergic receptor (beta(1)-AR) subtype linked to the activation of adenylyl cyclase and the accumulation of cyclic adenosine 3',5'-monophosphate (cAMP) in cardiomyocytes has been challenged by recent studies showing that cardiomyocytes co-express pharmacologically distinct beta(2)-AR subtypes that activate a more broad range of downstream effectors. While beta(1)- and beta(2)-ARs exert largely functionally equivalent cellular actions in heterologous expression systems, signaling by endogenous beta-AR subtypes in highly differentiated cells such as cardiomyocytes can be strikingly different. There is growing evidence that certain features of the signaling phenotypes for beta-AR subtypes in cardiomyocytes are inconsistent with traditional models that attribute signaling specificity to high-affinity protein-protein interactions between receptors, G-proteins, and effectors freely mobile on surface membranes. This chapter summarizes recent studies that focus on membrane microdomains (such as caveolae or lipid rafts) as sites that differentially localizing individual beta-AR subtypes as well as the downstream signaling machinery that generates, propagates, and downregulates the cAMP-protein kinase A signaling pathway. To the extent that this mechanism calibrates beta-AR responses in cardiomyocytes, it would be expected to be pertinent to the pathogenesis of heart failure, where chronic/persistent beta-AR signaling contributes to ventricular remodeling and impacts on long-term survival.
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 West 168 Street, NY 10032, USA. sfs1@columbia.edu
Susan F
SF
Steinberg
D000818:Animals; D021941:Caveolae / Q000378:metabolism* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D015398:Signal Transduction
D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP