Subtype-specific [beta]-adrenoceptor signaling pathways in the heart and their potential clinical implications

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