IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels

Abstract

TRPA1 channels have been implicated in mechanical and cold hypersensitivity in chronic pain. But how TRPA1 mediates this process is unclear. Here we show that IQ motif containing GTPase activating protein 1 is responsible using a combination of biochemical, molecular, Ca2+ imaging and behavioural approaches. TRPA1 and IQ motif containing GTPase activating protein 1 bind to each other and are highly colocalized in sensory dorsal root ganglia neurons in mice. The expression of IQ motif containing GTPase activating protein 1 but not TRPA1 is increased in chronic inflammatory and neuropathic pain. However, TRPA1 undergoes increased trafficking to the membrane of dorsal root ganglia neurons catalysed by the small GTPase Cdc42 associated with IQ motif containing GTPase activating protein 1, leading to functional sensitization of the channel. Activation of protein kinase A is also sufficient to evoke TRPA1 trafficking and sensitization. All these responses are, however, completely prevented in the absence of IQ motif containing GTPase activating protein 1. Concordantly, deletion of IQ motif containing GTPase activating protein 1 markedly reduces mechanical and cold hypersensitivity in chronic inflammatory and neuropathic pain in mice. IQ motif containing GTPase activating protein 1 thus promotes chronic pain by coupling the trafficking and signalling machineries to TRPA1 channels.

Publication DOI: https://doi.org/10.1093/brain/awac462
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
Funding Information: This work was funded by Biotechnology and Biological Sciences Research Council (BBSRC), UK (BB/T01668X/1 to X.Z.), Medical Research Council (MRC), UK (MR/V004077/1 to X.Z.) and Versus Arthritis UK (21971 to X.Z.). We are grateful to Dr David Sacks (Depart
Additional Information: © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited This AAM will be replaced by the VoR at the same DOI when the VoR is published
Uncontrolled Keywords: IQGAP1,TRPA1,calcium signalling,inflammatory pain,neuropathic pain,protein trafficking,Clinical Neurology
Publication ISSN: 0006-8950
Last Modified: 16 May 2024 07:16
Date Deposited: 16 Dec 2022 09:46
Full Text Link:
Related URLs: https://academi ... 565?login=false (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2023-06-01
Published Online Date: 2022-12-07
Accepted Date: 2022-11-24
Authors: Khan, Shakil
Patra, Pabitra H
Somerfield, Hannah
Benya-Aphikul, Hattaya
Upadhya, Manoj (ORCID Profile 0000-0002-2032-1472)
Zhang, Xuming

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