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IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels
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Khan, Shakil, Patra, Pabitra H., Somerfield, Hannah, Benya-Aphikul, Hattaya, Upadhya, Manoj and Zhang, Xuming (2022) IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels. Brain . doi:10.1093/brain/awac462 ISSN 0006-8950. (In Press)
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WRAP-IQGAP1-promotes-chronic-pain-regulating-trafficking-sensitization-TRPA1-channels-2022.pdf - Accepted Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (2597Kb) | Preview |
Official URL: http://dx.doi.org/10.1093/brain/awac462
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 (IQGAP1) is responsible using a combination of biochemical, molecular, Ca2+ imaging and behavioural approaches. TRPA1 and IQGAP1 bind to each other and are highly colocalised in sensory DRG neurons in mice. The expression of IQGAP1 but not TRPA1 is increased in chronic inflammatory and neuropathic pain. However, TRPA1 undergoes increased trafficking to the membrane of DRG neurons catalysed by the small GTPase Cdc42 associated with IQGAP1, leading to functional sensitization of the channel. Activation of PKA is also sufficient to evoke TRPA1 trafficking and sensitization. All these responses are, however, completely prevented in the absence of IQGAP1. Concordantly, deletion of IQGAP1 markedly reduces mechanical and cold hypersensitivity in chronic inflammatory and neuropathic pain in mice. IQGAP1 thus promotes chronic pain by coupling the trafficking and signalling machineries to TRPA1 channels.
| Item Type: | Journal Article | ||||||||||||
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| Subjects: | Q Science > QP Physiology R Medicine > RB Pathology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||||||
| Library of Congress Subject Headings (LCSH): | TRP channels, G proteins , G proteins -- Physiological effect , Proteins -- Physiological transport, Calcium -- Physiological effect, Intracellular calcium, Chronic pain -- Psychological aspects | ||||||||||||
| Journal or Publication Title: | Brain | ||||||||||||
| Publisher: | Oxford University Press | ||||||||||||
| ISSN: | 0006-8950 | ||||||||||||
| Official Date: | 7 December 2022 | ||||||||||||
| Dates: |
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| DOI: | 10.1093/brain/awac462 | ||||||||||||
| Status: | Peer Reviewed | ||||||||||||
| Publication Status: | In Press | ||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||
| Date of first compliant deposit: | 15 December 2022 | ||||||||||||
| Date of first compliant Open Access: | 16 December 2022 | ||||||||||||
| RIOXX Funder/Project Grant: |
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