Heterodimerization of 1- and 2-Adrenergic Receptor Subtypes Optimizes -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 -adrenergic receptor ( AR) subtypes expressed in the heart, 1AR, and 2AR, and its physiological relevance. In intact adult-mouse cardiac myocytes lacking native 1AR and 2AR, coexpression of both 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 AR 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 AR subtypes resulted in sensitization of these receptors in response to agonist stimulation. In contrast, the presence of 1AR greatly suppressed ligand-independent spontaneous activity of coexisting 2ARs. Thus, heterodimerization of 1AR and 2AR in intact cardiac myocytes creates a novel population of ARs with distinct functional and pharmacological properties, resulting in enhanced signaling efficiency in response to agonist stimulation while silencing ligandindependent receptor activation, thereby optimizing -adrenergic modulation of cardiac contractility. (Circ Res. 2005;97:244-251.)