β-Adrenergic receptor subtype signaling in heart: From bench to bedside

beta-adrenergic receptor (beta AR) stimulation by the sympathetic nervous system or circulating catecholamines is broadly involved in peripheral blood circulation, metabolic regulation, muscle contraction, and central neural activities. In the heart, acute beta AR stimulation serves as the most powerful means to regulate cardiac output in response to a fight-or-flight situation, whereas chronic beta AR stimulation plays an important role in physiological and pathological cardiac remodeling. There are three beta AR subtypes, beta(1)AR, beta(2)AR and beta(3)AR, in cardiac myocytes. Over the past two decades, we systematically investigated the molecular and cellular mechanisms underlying the different even opposite functional roles of beta(1)AR and beta(2)AR subtypes in regulating cardiac structure and function, with keen interest in the development of novel therapies based on our discoveries. We have made three major discoveries, including (1) dual coupling of beta(2)AR to G(s) and G(i) proteins in cardiomyocytes, (2) cardioprotection by beta(2)AR signaling in improving cardiac function and myocyte viability, and (3) PKA-independent, CaMKII-mediated beta(1)AR apoptotic and maladaptive remodeling signaling in the heart. Based on these discoveries and salutary effects of beta(1)AR blockade on patients with heart failure, we envision that activation of beta(2)AR in combination with clinically used beta(1)AR blockade should provide a safer and more effective therapy for the treatment of heart failure.