The myocardium-protective Gly-49 variant of the beta 1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation.

• The beta(1)-adrenergic receptor (beta(1)AR) 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 beta(1)AR (Gly-49-beta(1)AR) 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-beta(1)AR demonstrated characteristic features of constitutively active receptors. In cells expressing the Gly-49-beta(1)AR, both basal and agonist-stimulated adenylyl cyclase activities were higher than in cells expressing the Ser-49 variant (Ser-49-beta(1)AR). The Gly-49-beta(1)AR 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-beta(1)AR than on those expressing the Ser-49-beta(1)AR. 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-beta(1)AR also displayed a more profound agonist-promoted down-regulation than the Ser-49 variant. The stronger regulation of the Gly-49-beta(1)AR could explain the beneficial effect of the Gly-49 genotypes on survival, further supporting the concept that beta(1)AR desensitization is protective in heart failure.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

Down-Regulation

GTP-Binding Proteins

physiology

Genotype

Glycine

Heart Failure

drug therapy

mortality

physiopathology

Humans

Metoprolol

pharmacology

Polymorphism

Genetic

Receptors

Adrenergic

beta-1

chemistry

genetics

physiology

Structure-Activity Relationship

Publication and Content Type

ref (subject category)

art (subject category)