Recent advances in cardiac beta(2)-adrenergic signal transduction

Recent studies have added complexities to the conceptual framework of cardi ac beta-adrenergic receptor (beta-AR) signal transduction. Whereas the clas sical linear G(s)-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling ca scade has been corroborated for beta(1)-AR stimulation, the beta(2)-AR sign aling pathway bifurcates at the very first postreceptor step, the G protein level. Ln addition to G(s), beta(2)-AR couples to pertussis toxin-sensitiv e G(i) proteins, G(i2) and G(i3). The coupling of beta(2)-AR to G(i) protei ns mediates, to a large extent, the differential actions of the beta-AR sub types on cardiac Ca2+ handling, contractility, cAMP accumulation, and PKA-m ediated protein phosphorylation. The extent of G(i) coupling in ventricular myocytes appears to be the basis of the substantial species-to-species div ersity in beta(2)-AR-mediated cardiac responses. There is an apparent disso ciation of beta(2)-AR-induced augmentations of the intracellular Ca2+ (Ca-i ) transient and contractility from cAMP production and PKA-dependent cytopl asmic protein phosphorylation. This can be largely explained by G(i)-depend ent functional compartmentalization of the beta(2)-AR-directed cAMP/PKA sig naling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during P\bet a-AR subtype stimulation. Emerging evidence also points to distinctly diffe rent roles of these beta-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specific ity of beta-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of beta-AR sub types in healthy and diseased hearts.