The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons.

التفاصيل البيبلوغرافية
العنوان:	The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons.
المؤلفون:	Arcas JM; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain., Oudaha K; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain., González A; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain., Fernández-Trillo J; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain., Peralta FA; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain., Castro-Marsal J; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain., Poyraz S; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain., Taberner F; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain., Sala S; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain., de la Peña E; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain., Gomis A; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain., Viana F; Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain.
المصدر:	British journal of pharmacology [Br J Pharmacol] 2024 Sep; Vol. 181 (17), pp. 3192-3214. Date of Electronic Publication: 2024 May 13.
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE
أسماء مطبوعة:	Publication: London : Wiley Original Publication: London, Macmillian Journals Ltd.
مواضيع طبية MeSH:	TRPM Cation Channels/antagonists & inhibitors , TRPM Cation Channels/metabolism , Sirolimus/pharmacology , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/metabolism , Immunosuppressive Agents/pharmacology , Mice, Knockout*, Animals ; Humans ; HEK293 Cells ; Rats ; Mice ; Male ; Mice, Inbred C57BL ; Cells, Cultured ; Calcium/metabolism ; Ganglia, Spinal/drug effects ; Ganglia, Spinal/metabolism ; Cold Temperature
مستخلص:	Background and Purpose: The mechanistic target of rapamycin (mTOR) signalling pathway is a key regulator of cell growth and metabolism. Its deregulation is implicated in several diseases. The macrolide rapamycin, a specific inhibitor of mTOR, has immunosuppressive, anti-inflammatory and antiproliferative properties. Recently, we identified tacrolimus, another macrolide immunosuppressant, as a novel activator of TRPM8 ion channels, involved in cold temperature sensing, thermoregulation, tearing and cold pain. We hypothesized that rapamycin may also have agonist activity on TRPM8 channels. Experimental Approach: Using calcium imaging and electrophysiology in transfected HEK293 cells and wildtype or Trpm8 KO mouse DRG neurons, we characterized rapamycin's effects on TRPM8 channels. We also examined the effects of rapamycin on tearing in mice. Key Results: Micromolar concentrations of rapamycin activated rat and mouse TRPM8 channels directly and potentiated cold-evoked responses, effects also observed in human TRPM8 channels. In cultured mouse DRG neurons, rapamycin increased intracellular calcium levels almost exclusively in cold-sensitive neurons. Responses were markedly decreased in Trpm8 KO mice or by TRPM8 channel antagonists. Cutaneous cold thermoreceptor endings were also activated by rapamycin. Topical application of rapamycin to the eye surface evokes tearing in mice by a TRPM8-dependent mechanism. Conclusion and Implications: These results identify TRPM8 cationic channels in sensory neurons as novel molecular targets of the immunosuppressant rapamycin. These findings may help explain some of its therapeutic effects after topical application to the skin and the eye surface. Moreover, rapamycin could be used as an experimental tool in the clinic to explore cold thermoreceptors. (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
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معلومات مُعتمدة:	GRISOLIA/2019/089 Generalitat Valenciana; PROMETEO/2021/03 Generalitat Valenciana; CEX2021-001165-S Ministerio de Ciencia e Innovación; PID2019-108194RB-I00/AEI/10.13039/501100011033 Ministerio de Ciencia e Innovación; JAEINT_22_01043 Consejo Superior de Investigaciones Científicas; ionRAPA Grant Fundacion ICAR; European Regional Development Fund
فهرسة مساهمة:	Keywords: ageing; cold; dry eye disease; mTOR; pain; thermoregulation
المشرفين على المادة:	0 (TRPM Cation Channels) W36ZG6FT64 (Sirolimus) 0 (TRPM8 protein, mouse) 0 (Immunosuppressive Agents) SY7Q814VUP (Calcium) 0 (TRPM8 protein, human)
تواريخ الأحداث:	Date Created: 20240514 Date Completed: 20240802 Latest Revision: 20240802
رمز التحديث:	20240802
DOI:	10.1111/bph.16402
PMID:	38741464
قاعدة البيانات:	MEDLINE

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