title: Whirlin increases TRPV1 channel expression and cellular stability.
abstract: The expression and function of TRPV1 are influenced by its interaction with cellular proteins. Here, we identify Whirlin, a cytoskeletal PDZ-scaffold protein implicated in hearing, vision and mechanosensory transduction, as an interacting partner of TRPV1. Whirlin associates with TRPV1 in cell lines and in primary cultures of rat nociceptors. Whirlin is expressed in 55% of mouse sensory C-fibers, including peptidergic and non-peptidergic nociceptors, and co-localizes with TRPV1 in 70% of them. Heterologous expression of Whirlin increased TRPV1 protein expression and trafficking to the plasma membrane, and promoted receptor clustering. Silencing Whirlin expression with siRNA or blocking protein translation resulted in a concomitant degradation of TRPV1 that could be prevented by inhibiting the proteasome. The degradation kinetics of TRPV1 upon arresting protein translation mirrored that of Whirlin in cells co-expressing both proteins, suggesting a parallel degradation mechanism. Noteworthy, Whirlin expression significantly reduced TRPV1 degradation induced by prolonged exposure to capsaicin. Thus, our findings indicate that Whirlin and TRPV1 are associated in a subset of nociceptors and that TRPV1 protein stability is increased through the interaction with the cytoskeletal scaffold protein. Our results suggest that the Whirlin–TRPV1 complex may represent a novel molecular target and its pharmacological disruption might be a therapeutic strategy for the treatment of peripheral TRPV1-mediated disorders.
authors.affiliation: Instituto de Biología Molecular y Celular. Universitas Miguel Hernández, Alicante, Spain; Centro de Investigaciones Príncipe Felipe, Valencia, Spain.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Ciardo
authors.affiliation: Centro de Investigaciones Príncipe Felipe, Valencia, Spain.
authors.forename: Amparo
authors.initials: A
authors.lastname: Andrés-Bordería
authors.affiliation: Instituto de Biología Molecular y Celular. Universitas Miguel Hernández, Alicante, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Cuesta
authors.affiliation: Instituto de Biología Molecular y Celular. Universitas Miguel Hernández, Alicante, Spain.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Valente
authors.affiliation: Instituto de Biología Molecular y Celular. Universitas Miguel Hernández, Alicante, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Camprubí-Robles
authors.affiliation: John A Moran Eye Center, The University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Centro de Investigaciones Príncipe Felipe, Valencia, Spain. Electronic address: Rosa.Planells-Cases@mdc-berlin.de.
authors.forename: Rosa
authors.initials: R
authors.lastname: Planells-Cases
authors.affiliation: Instituto de Biología Molecular y Celular. Universitas Miguel Hernández, Alicante, Spain. Electronic address: aferrer@umh.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009619:Nociceptors / Q000166:cytology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D050916:TRPV Cation Channels / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; C477218:Whrn protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: Cytoskeleton; Nociception; PDZ; Pain; Synapsis; Thermosensory