The Role of Sequestration in G Protein-coupled Receptor Resensitization

• Published in: The Journal of biological chemistry Vol. 272; no. 1; pp. 5 - 8
• Main Authors: Krueger, Kathleen M., Daaka, Yehia, Pitcher, Julie A., Lefkowitz, Robert J.
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 01.01.1997
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.1.5

G protein-coupled receptor kinases phosphorylate the agonist occupied conformation of G protein-coupled receptors in the plasma membrane, leading to their desensitization. Receptor resensitization requires receptor dephosphorylation, a process which is mediated by a plasma and vesicular membrane-associated form of PP-2A. We present evidence that, like receptor phosphorylation, receptor dephosphorylation is tightly regulated, requiring a specific receptor conformation induced by vesicular acidification. In vitro , spontaneous dephosphorylation of phosphorylated receptors is observed only at acidic pH. Furthermore, in intact cells upon agonist stimulation, phosphorylated receptors traffic from the plasma membrane to vesicles where they become physically associated with the phosphatase and dephosphorylated. Treatment of cells with NH 4 Cl, which disrupts the acidic pH found in endosomal vesicles, blocks association of the receptors with the phosphatase and blocks receptor dephosphorylation. These findings suggest that a conformational change in the receptor induced by acidification of the endosomal vesicles is the key determinant regulating receptor dephosphorylation and resensitization.