Heterodimerization of β1- and β2-adrenergic receptor subtypes optimizes β-adrenergic modulation of cardiac contractility

Intermolecular interactions between members of both similar and divergent G protein-coupled receptor subfamilies have been shown in various experimental systems. Here, we demonstrate heterodimerization of predominant beta-adrenergic receptor (beta AR) subtypes expressed in the heart, beta(1)AR, and beta(2)AR, and its physiological relevance. In intact adult-mouse cardiac myocyte slacking native beta(1)AR and beta(2)AR, coexpression of both beta AR subtypes led to receptor heterodimerization, as evidenced by their coimmunoprecipitation, colocalization at optical resolution, and markedly increased binding affinity for subtype-selective ligands. As a result, the dose-response curve of myocyte contraction to beta AR agonist stimulation with isoproterenol (ISO) was shifted leftward by approximate to 1.5 orders of magnitude, and the response of cellular cAMP formation to ISO was enhanced concomitantly, indicating that intermolecular interactions of beta AR subtypes resulted in sensitization of these receptors in response to agonist stimulation. In contrast, the presence of beta(1)AR greatly suppressed ligand-independent spontaneous activity of coexisting beta(2)ARs. Thus, heterodimerization of beta(1)AR and beta(2)AR in intact cardiac myocytes creates a novel population of beta ARs with distinct functional and pharmacological properties, resulting in enhanced signaling efficiency in response to agonist stimulation while silencing ligand-independent receptor activation, thereby optimizing beta-adrenergic modulation of cardiac contractility.