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

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, Ca(2+) imaging and behavioural...

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Autores principales: Khan, Shakil, Patra, Pabitra Hriday, Somerfield, Hannah, Benya-Aphikul, Hattaya, Upadhya, Manoj, Zhang, Xuming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232262/
https://www.ncbi.nlm.nih.gov/pubmed/36477832
http://dx.doi.org/10.1093/brain/awac462
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author Khan, Shakil
Patra, Pabitra Hriday
Somerfield, Hannah
Benya-Aphikul, Hattaya
Upadhya, Manoj
Zhang, Xuming
author_facet Khan, Shakil
Patra, Pabitra Hriday
Somerfield, Hannah
Benya-Aphikul, Hattaya
Upadhya, Manoj
Zhang, Xuming
author_sort Khan, Shakil
collection PubMed
description 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, Ca(2+) 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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spelling pubmed-102322622023-06-01 IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels Khan, Shakil Patra, Pabitra Hriday Somerfield, Hannah Benya-Aphikul, Hattaya Upadhya, Manoj Zhang, Xuming Brain Original Article 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, Ca(2+) 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. Oxford University Press 2022-12-07 /pmc/articles/PMC10232262/ /pubmed/36477832 http://dx.doi.org/10.1093/brain/awac462 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/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.
spellingShingle Original Article
Khan, Shakil
Patra, Pabitra Hriday
Somerfield, Hannah
Benya-Aphikul, Hattaya
Upadhya, Manoj
Zhang, Xuming
IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels
title IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels
title_full IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels
title_fullStr IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels
title_full_unstemmed IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels
title_short IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels
title_sort iqgap1 promotes chronic pain by regulating the trafficking and sensitization of trpa1 channels
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232262/
https://www.ncbi.nlm.nih.gov/pubmed/36477832
http://dx.doi.org/10.1093/brain/awac462
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