MDFIC2 is a PIEZO channel modulator that can alleviate mechanical allodynia associated with neuropathic pain
PIEZO channels are mechanical force sensors involved in various biological processes, including somatosensation. To date, only a few PIEZO-binding partners have been identified, including MyoD-family inhibitor proteins (MDFI and MDFIC). Here, we show that MDFIC2, a third member of the MDFI protein family with an as-yet-unknown function, is expressed in a subset of nociceptive sensory neurons. MDFIC2 modulates both PIEZO1 and PIEZO2 gating properties by slowing their kinetics and shifting mechanical sensitivity to higher forces. Interestingly, <i>Mdfic2</i> is downregulated in mouse neuropathic pain models in which mechanical allodynia is a hallmark symptom. We found that intrathecal administration of adeno-associated virus vector encoding <i>MDFIC2</i> cDNA reduces mechanical sensitivity and attenuates mechanical allodynia in the spared nerve injury neuropathic pain model. These findings demonstrate a mechanism for regulating mechanosensation and highlight a potential therapeutic route for treating mechanical allodynia.
Authors
- James J. Cox (ORCID: https://orcid.org/0000-0002-9129-8011)
- Jing Zhao (ORCID: https://orcid.org/0000-0003-2587-1198)
- Bertrand Coste (ORCID: https://orcid.org/0000-0002-0163-2494)
- Samuel J. Gossage (ORCID: https://orcid.org/0009-0005-6020-5029)
- Ahad A. Rahim (ORCID: https://orcid.org/0000-0003-0044-0949)
- Jesús M. Torres (ORCID: https://orcid.org/0000-0001-9361-6258)
- John N. Wood (ORCID: https://orcid.org/0000-0002-9166-8158)
- Nancy Osorio (ORCID: https://orcid.org/0009-0006-6368-7569)
- Sonia Santana‐Varela (ORCID: https://orcid.org/0000-0002-6063-8669)
- Andrei L. Okorokov (ORCID: https://orcid.org/0000-0003-2477-3254)
- Abdella M. Habib (ORCID: https://orcid.org/0000-0001-7453-3932)
- Virginie Pénalba (ORCID: https://orcid.org/0009-0008-2641-4339)
- Shengnan Li (ORCID: https://orcid.org/0000-0002-0257-4708)
- Xuelong Zhou (ORCID: https://orcid.org/0009-0000-8241-5995)
- Chenjing Zhang (ORCID: https://orcid.org/0000-0003-1476-2682)
- Jun Zhou (ORCID: https://orcid.org/0009-0009-6952-8325)
- Amy Geard (ORCID: https://orcid.org/0000-0001-5127-0922)
- Mengyue Ji
- A Mahmoud (ORCID: https://orcid.org/0009-0001-8087-2567)
- Mehdi A. Rezai
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Universidad de Granada (ES)
- Wolfson Foundation (GB)
- Wuhan University (CN)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Children's Hospital of Zhejiang University (CN)
- Zhejiang Hospital (CN)
- Délégation Provence et Corse (FR)
- Women's Hospital, School of Medicine, Zhejiang University (CN)
- Renmin Hospital of Wuhan University (CN)
- Woman's Hospital (US)
- Canadian Nautical Research Society (CA)
- Hangzhou Medical College (CN)
- University College London (GB)
- Qatar University (QA)
- Assiut University (EG)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-11-07
- DOI
- https://doi.org/10.1073/pnas.2512426122
- Citations
- 4
- Primary Topic
- Erythrocyte Function and Pathophysiology
- Type
- article
- Field-Weighted Citation Impact
- 4.66
Funders
- Aix-Marseille Université
- Wellcome Trust
- National Institute for Health and Care Research
- University College London
- European Commission
- Institut National de la Santé et de la Recherche Médicale
- National Natural Science Foundation of China
- Fonds National de la Recherche Luxembourg
- Qatar University
- Centre National de la Recherche Scientifique
- Zhejiang University
- Universidad de Granada
- Wuhan University
- Assiut University
- Qatar National Research Fund
- Medical Research Council
- School of Pharmacy, University College London
- Faculty of Medicine, Assiut University
- Renmin Hospital of Wuhan University
- Natural Science Foundation of Zhejiang Province