Emerging concepts and therapeutic implications of β-adrenergic receptor subtype signaling

The stimulation of β-adrenergic receptor (βAR) plays a pivotal role in regulating myocardial function and morphology in the normal and failing heart. Three genetically and pharmacologically distinct βAR subtypes, β1AR, β2AR, and β3AR, are identified in various types of cells. While both β1AR and β2AR, the predominant βAR subtypes expressed in the heart of many mammalian species including human, are coupled to the Gs-adenylyl cyclase-cAMP-PKA pathway, β2AR dually activates pertussis toxin-sensitive Gi proteins. During acute stimulation, β2AR-Gi coupling partially inhibits the Gs-mediated positive contractile and relaxant effects via a Gi-Gβγ-phosphoinositide 3-kinase (PI3K)-dependent mechanism in adult rodent cardiomyocytes. More importantly, persistent β1AR stimulation evokes a multitude of cardiac toxic effects, including myocyte apoptosis and hypertrophy, via a calmodulin-dependent protein kinase II (CaMKII)-, rather than cAMP-PKA-, dependent mechanism in rodent heart in vivo and cultured cardiomyocytes. In contrast, persistent β2AR activation protects myocardium by a cell survival pathway involving Gi, PI3K, and Akt. In this review, we attempt to highlight the distinct functionalities and signaling mechanisms of these βAR subtypes and discuss how these subtype-specific properties of βARs might affect the pathogenesis of congestive heart failure (CHF) and the therapeutic effectiveness of certain β-blockers in the treatment of congestive heart failure.