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

Abstract

β-adrenergic receptor (βAR) 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 βAR stimulation serves as the most powerful means to regulate cardiac output in response to a fight-or-flight situation, whereas chronic βAR stimulation plays an important role in physiological and pathological cardiac remodeling.There are three βAR subtypes, β(1)AR, β(2)AR and β(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 β(1)AR and β(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 β(2)AR to G(s) and G(i) proteins in cardiomyocytes, (2) cardioprotection by β(2)AR signaling in improving cardiac function and myocyte viability, and (3) PKA-independent, CaMKII-mediated β(1)AR apoptotic and maladaptive remodeling signaling in the heart. Based on these discoveries and salutary effects of β(1)AR blockade on patients with heart failure, we envision that activation of β(2)AR in combination with clinically used β(1)AR blockade should provide a safer and more effective therapy for the treatment of heart failure.

Figure 1

Development of the receptor theory. In the classical paradigm, ligands have linear efficacies, referring to their abilities to stabilize the receptor into a single active state. The emerging concept of biased agonism suggests that a biased ligand may stabilize the receptor into a distinct active state that does not activate G proteins but activates β-arrestins. In the concept of functional selectivity, receptors may exist in multiple active conformations as stabilized by different ligands, and each of these conformations gives rise to different downstream signals and biological effects. βArr, β-arrestin; L, ligand; R, inactive conformation of GPCR; R^*, active conformation of GPCR.