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J Biol Chem. 2012 Oct 26;287(44):37552-63. doi: 10.1074/jbc.M112.391847. Epub 2012 Sep 5.

β-Arrestin-2 desensitizes the transient receptor potential vanilloid 1 (TRPV1) channel.

Author information

1
Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas 78229, USA.

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel activated by multiple stimuli and is implicated in a variety of pain disorders. Dynamic sensitization of TRPV1 activity by A-kinase anchoring protein 150 demonstrates a critical role for scaffolding proteins in nociception, yet few studies have investigated scaffolding proteins capable of mediating receptor desensitization. In this study, we identify β-arrestin-2 as a scaffolding protein that regulates TRPV1 receptor activity. We report β-arrestin-2 association with TRPV1 in multiple cell models. Moreover, siRNA-mediated knockdown of β-arrestin-2 in primary cultures resulted in a significant increase in both initial and repeated responses to capsaicin. Electrophysiological analysis further revealed significant deficits in TRPV1 desensitization in primary cultures from β-arrestin-2 knock-out mice compared with wild type. In addition, we found that β-arrestin-2 scaffolding of phosphodiesterase PDE4D5 to the plasma membrane was required for TRPV1 desensitization. Importantly, inhibition of PDE4D5 activity reversed β-arrestin-2 desensitization of TRPV1. Together, these results identify a new endogenous scaffolding mechanism that regulates TRPV1 ligand binding and activation.

PMID:
22952227
PMCID:
PMC3481349
DOI:
10.1074/jbc.M112.391847
[Indexed for MEDLINE]
Free PMC Article

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