Subtype-specific β-adrenoceptor signaling pathways in the heart and their potential clinical implications

Abstract β-Adrenoceptor stimulation serves as the most powerful means to increase cardiac output in response to stress or exercise. However, sustained β-adrenoceptor stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy and apoptosis, thus contributing to heart failure. Coexisting cardiac β-adrenoceptor subtypes, mainly β 1 -adrenoceptors and β 2 -adrenoceptors, activate different signaling cascades with β 1 -adrenoceptors coupling to G s and β 2 -adrenoceptors coupling to G s and G i pathways. As a result, sustained β 2 -adrenoceptor stimulation protects cardiomyocytes against apoptosis via a G i –phosphatidylinositol 3-kinase–protein kinase B pathway, whereas chronic β 1 -adrenoceptor stimulation induces myocyte hypertrophy and apoptosis by protein kinase A-independent activation of calmodulin kinase II signaling. These advances in our understanding of β-adrenoceptor subtype signaling identify the mechanisms that underlie the beneficial effects of β-adrenoceptor antagonists and delineate the rationale for combining β 1 -adrenoceptor blockade with β 2 -adrenoceptor activation as a potential therapy for heart failure.