Polymorphic Deletion of Three Intracellular Acidic Residues of the α2B-Adrenergic Receptor Decreases G Protein-coupled Receptor Kinase-mediated Phosphorylation and Desensitization

• Published in: The Journal of biological chemistry 2001-02, Vol.276 (7), p.4917
• Main Authors: Kersten M. Small, Kari M. Brown, Susan L. Forbes, Stephen B. Liggett
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M008118200

A polymorphic variant of the human α 2B -adrenergic receptor (α 2B AR), which consists of a deletion of three glutamic acids (residues 301–303) in the third intracellular loop was found to be common in Caucasians (31%) and to a lesser extent in African-Americans (12%). The consequences of this deletion were assessed by expressing wild-type and the Del301–303 receptors in Chinese hamster ovary and COS cells. Ligand binding was not affected, although a small decrease in coupling efficiency to the inhibition of adenylyl cyclase was observed with the mutant. The deletion occurs within a stretch of acidic residues that is thought to establish the milieu for agonist-promoted phosphorylation and desensitization of the receptor by G protein-coupled receptor kinases (GRKs). Agonist-promoted phosphorylation studies carried out in cells coexpressing the α 2B ARs and GRK2 revealed that the Del301–303 receptor displayed ∼56% of wild-type phosphorylation. Furthermore, the depressed phosphorylation imposed by the deletion was found to result in a complete loss of short term agonist-promoted receptor desensitization. Thus the major phenotype of the Del301–303 α 2B AR is one of impaired phosphorylation and desensitization by GRKs, and thus the polymorphisms renders the receptor incapable of modulation by this key mechanism of dynamic regulation.