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

doi:10.1093/brain/awac462

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 journal › Article › peer-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 language	English
Article number	2595
Pages (from-to)	2595-2611
Number of pages	17
Journal	Brain
Volume	146
Issue number	6
Early online date	7 Dec 2022
DOIs	https://doi.org/10.1093/brain/awac462
Publication status	Published - 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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10.1093/brain/awac462Licence: CC BY 4.0

Khanetal_2022_AAM
© 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
Accepted author manuscript, 2.54 MBLicence: CC BY 4.0

Cite this

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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.",

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

Abstract

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