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| Regulation of V2 vasopressin receptor degradation by agonist-promoted ubiquitination |
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| Author(s): Martin NP, Lefkowitz RJ, Shenoy SK |
| Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 278 Issue: 46 Pages: 45954-45959 Published: NOV 14 2003 |
| Times Cited: 52 References: 23 |
| Abstract: The seven-transmembrane-spanning vasopressin V2 receptor (V2R) is a G(s)-coupled receptor that is rapidly phosphorylated and internalized following stimulation with the agonist, arginine-vasopressin. Herein, we show that the V2R is ubiquitinated following agonist stimulation. V2R-ubiquitination is not observed in a beta-arrestin1,2 deleted mouse fibroblast cell line and is restored following introduction of beta-arrestin2, thus indicating that beta-arrestin2 is required for the ubiquitination of V2R. A mutant V2R (K268R) that is not ubiquitinated still activates G(s) and internalizes with similar kinetics as the wild type receptor. Unstimulated wild type and K268R mutant receptors degrade at similar rates and have comparable half-lives of 217 +/- 17 and 245 +/- 29 min as determined by pulse-chase experiments. However, following agonist stimulation, the rate of receptor degradation for the wild type is enhanced (half-life of 69 +/- 19 min), whereas that of the mutant is only minimally affected (half-life of 188 +/- 11 min). These data suggest that V2R levels are regulated through at least two processes. In the absence of agonist stimulation, a slow degradative pathway operates that is independent of receptor ubiquitination. However, receptor stimulation leads to rapid beta-arrestin2-dependent ubiquitination of the receptor and increased degradation. |
| Document Type: Article |
| Language: English |
| Reprint Address: Lefkowitz, RJ (reprint author), Duke Univ, Med Ctr, Dept Med, Howard Hughes Med Inst, Durham, NC 27710 USA |
Addresses:
1. Duke Univ, Med Ctr, Dept Med, Howard Hughes Med Inst, Durham, NC 27710 USA
2. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA |
| Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: 741HH |
| ISSN: 0021-9258 |
| DOI: 10.1074/jbc.M308285200 |
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