The myocardium-protective Gly-49 variant of the β1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation

Abstract

The β1-adrenergic receptor (β1AR) is a major mediator of catecholamine effects in human heart. Patients with heart failure who were hetero- or homozygous for the Gly-49 variant of the β1AR (Gly-49-β1AR) showed improved long-term survival as compared with those with the Ser-49 genotype. Here, the functional consequences of this polymorphism were studied in cells expressing either variant. The Gly-49-β1AR demonstrated characteristic features of constitutively active receptors. In cells expressing the Gly-49-β1AR, both basal and agonist-stimulated adenylyl cyclase activities were higher than in cells expressing the Ser-49 variant (Ser-49-β1AR). The Gly-49-β1AR was more sensitive to the inhibitory effect of the inverse agonist metoprolol and displayed increased affinity for agonists. Isoproterenol potency for adenylyl cyclase activation was higher on membranes expressing the Gly-49-β1AR than on those expressing the Ser-49-β1AR. After incubation with saturating concentrations of catecholamines or sustained stimulation, the Gly-49 variant showed a much higher desensitization, which largely prevailed over constitutive activity in terms of cAMP accumulation. The Gly-49-β1AR also displayed a more profound agonist-promoted down-regulation than the Ser-49 variant. The stronger regulation of the Gly-49-β1AR could explain the beneficial effect of the Gly-49 genotypes on survival, further supporting the concept that β1AR desensitization is protective in heart failure.