Recent advances in cardiac beta(2)-adrenergic signal transduction.
Recent studies have added complexities to the conceptual framework of cardiac beta-adrenergic receptor (beta-AR) signal transduction. Whereas the classical linear G(s)-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling cascade has been corroborated for beta(1)-AR stimulation, the beta(2)-AR signaling pathway bifurcates at the very first postreceptor step, the G protein level. In addition to G(s), beta(2)-AR couples to pertussis toxin-sensitive G(i) proteins, G(i2) and G(i3). The coupling of beta(2)-AR to G(i) proteins mediates, to a large extent, the differential actions of the beta-AR subtypes on cardiac Ca(2+) handling, contractility, cAMP accumulation, and PKA-mediated protein phosphorylation. The extent of G(i) coupling in ventricular myocytes appears to be the basis of the substantial species-to-species diversity in beta(2)-AR-mediated cardiac responses. There is an apparent dissociation of beta(2)-AR-induced augmentations of the intracellular Ca(2+) (Ca(i)) transient and contractility from cAMP production and PKA-dependent cytoplasmic protein phosphorylation. This can be largely explained by G(i)-dependent functional compartmentalization of the beta(2)-AR-directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during beta-AR subtype stimulation. Emerging evidence also points to distinctly different roles of these beta-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specificity of beta-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of beta-AR subtypes in healthy and diseased hearts.
Xiao
R P
RP
Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, MD 21224, USA. XiaoR@grc.nia.nih.gov
Cheng
H
H
Zhou
Y Y
YY
Kuschel
M
M
Lakatta
E G
EG
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004285:Dogs; D019204:GTP-Binding Proteins / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000187:drug effects / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013045:Species Specificity
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D009124:Muscle Proteins; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D002118:Calcium