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

Shakil Khan, Pabitra H Patra, Hannah Somerfield, Hattaya Benya-Aphikul, Manoj Upadhya, Xuming Zhang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number2595
Pages (from-to)2595-2611
Number of pages17
JournalBrain
Volume146
Issue number6
Early online date7 Dec 2022
DOIs
Publication statusPublished - 1 Jun 2023

Bibliographical note

© 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

Keywords

  • IQGAP1
  • TRPA1
  • calcium signalling
  • inflammatory pain
  • neuropathic pain
  • protein trafficking

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