Emerging concepts and therapeutic implications of beta-adrenergic receptor subtype signaling.
The stimulation of beta-adrenergic receptor (betaAR) plays a pivotal role in regulating myocardial function and morphology in the normal and failing heart. Three genetically and pharmacologically distinct betaAR subtypes, beta1AR, beta2AR, and beta3AR, are identified in various types of cells. While both beta1AR and beta2AR, the predominant betaAR subtypes expressed in the heart of many mammalian species including human, are coupled to the Gs-adenylyl cyclase-cAMP-PKA pathway, beta2AR dually activates pertussis toxin-sensitive Gi proteins. During acute stimulation, beta2AR-Gi coupling partially inhibits the Gs-mediated positive contractile and relaxant effects via a Gi-Gbetagamma-phosphoinositide 3-kinase (PI3K)-dependent mechanism in adult rodent cardiomyocytes. More importantly, persistent beta1AR 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 beta2AR 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 betaAR subtypes and discuss how these subtype-specific properties of betaARs might affect the pathogenesis of congestive heart failure (CHF) and the therapeutic effectiveness of certain beta-blockers in the treatment of congestive heart failure.
Zheng
Ming
M
Institute of Cardiovascular Sciences, Peking University, Beijing 100083, People's Republic of China.
Zhu
Weizhong
W
Han
Qide
Q
Xiao
Rui-Ping
RP
D000818:Animals; D019204:GTP-Binding Proteins / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D009206:Myocardium / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction
D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins