title: β-Arrestin-2 desensitizes the transient receptor potential vanilloid 1 (TRPV1) channel.
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.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
authors.forename: Elaine D
authors.initials: ED
authors.lastname: Por
authors.forename: Sonya M
authors.initials: SM
authors.lastname: Bierbower
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Berg
authors.forename: Ruben
authors.initials: R
authors.lastname: Gomez
authors.forename: Armen N
authors.initials: AN
authors.lastname: Akopian
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: Nathaniel A
authors.initials: NA
authors.lastname: Jeske
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016466:CHO Cells; D006224:Cricetinae; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism* / Q000502:physiology; D055785:Gene Knockdown Techniques; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D061251:Primary Cell Culture; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000502:physiology*; D050916:TRPV Cation Channels / Q000378:metabolism* / Q000502:physiology; D046509:Tissue Culture Techniques; D012668:Trigeminal Ganglion / Q000166:cytology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605258:Arrb2 protein, mouse; C000605257:Arrb2 protein, rat; D019390:Arrestins; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C531980:PDE4D protein, mouse