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 b-adrenergic receptor (bAR) subtypes expressed in the heart, b1AR and b2AR, and its physiological relevance. In intact adult mouse cardiac myocytes lacking native b1AR and b2AR, co-expression of both bAR subtypes led to receptor heterodimerization, as evidenced by their co-immunoprecipitation, co-localization at optical resolution, and markedly increased binding affinity for subtype-selective ligands. As a result, the dose-response curve of myocyte contraction to bAR agonist stimulation with isoproterenol (ISO) was shifted leftward by ~1.5 orders of magnitude, and the response of cellular cAMP formation to ISO was enhanced concomitantly, indicating that intermolecular interactions of bAR subtypes resulted in sensitization of these receptors in response to agonist stimulation. In contrast, the presence of b1AR greatly suppressed ligand-independent spontaneous activity of co-existing b2ARs. Thus, heterodimerization of b1AR and b2AR in intact cardiac myocytes creates a novel population of bARs with distinct functional and pharmacological properties, resulting in enhanced signaling efficiency in response to agonist stimulation while silencing ligand-independent receptor activation, thereby optimizing b-adrenergic modulation of cardiac contractility.
