Recent advances in cardiac β₂-adrenergic signal transduction

Recent studies have added complexities to the conceptual framework of cardiac β-adrenergic receptor (β-AR) signal transduction. Whereas the classical linear G(s)-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling cascade has been corroborated for β₁-AR stimulation, the β₂-AR signaling pathway bifurcates at the very first postreceptor step, the G protein level. In addition to G(s), β₂-AR couples to pertussis toxin-sensitive G(i) proteins, G(i)₂ and G(i)₃. The coupling of β₂-AR to G(i) proteins mediates, to a large extent, the differential actions of the β-AR subtypes on cardiac Ca²⁺ 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 β₂-AR-mediated cardiac responses. There is an apparent dissociation of β₂-AR-induced augmentations of the intracellular Ca²⁺ (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 β₂-AR-directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during β- AR subtype stimulation. Emerging evidence also points to distinctly different roles of these β-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specificity of β-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of β-AR subtypes in healthy and diseased hearts.