β-adrenergic receptor desensitization in cardiac disease:: Insights from gene-targeted mice

beta-Adrenergic receptors (beta ARs) belong to the large family of G-protein-coupled receptors that form the interface between the sympathetic nervous system and the cardiovascular system. Binding of beta-agonists to the beta AR leads to activation of adenylyl cyclase, generating cAMP and activating cAMP-dependent protein kinase A (PKA). Phosphorylation of critical regulatory proteins by PKA acts in concert to increase the rate of contraction, peak force, and the rate of relaxation. The regulation of myocardial beta ARs involves a process characterized by a rapid loss of receptor responsiveness despite continued presence of agonist. Chronic human heart failure is characterized by marked beta AR receptor desensitization as the result of both diminished beta AR number (receptor downregulation) and impaired beta AR function (receptor uncoupling). This review focuses on some recent studies using gene-targeted mouse models to understand the role of the beta AR system in pathological conditions of cardiac hypertrophy and heart failure.