期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 44, 页码 37552-37563出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.391847
关键词
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资金
- National Institutes of Health [T32 HL07446-29, R21 NS055835, F31 DE022517-01, RO1 NS061884]
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 beta-arrestin-2 as a scaffolding protein that regulates TRPV1 receptor activity. We report beta-arrestin-2 association with TRPV1 in multiple cell models. Moreover, siRNA-mediated knockdown of beta-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 beta-arrestin-2 knock-out mice compared with wild type. In addition, we found that beta-arrestin-2 scaffolding of phosphodiesterase PDE4D5 to the plasma membrane was required for TRPV1 desensitization. Importantly, inhibition of PDE4D5 activity reversed beta-arrestin-2 desensitization of TRPV1. Together, these results identify a new endogenous scaffolding mechanism that regulates TRPV1 ligand binding and activation.
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