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Becker, Jasmin ; Ellerkmann, Clara S. ; Schmelzer, Hannah ; Hermann, Christian ; Lützel, Kyra ; Gudermann, Thomas ; Konrad, David B. ; Trauner, Dirk ; Storch, Ursula ; Mederos y Schnitzler, Michael

Optical Control of TRPM8 Channels with Photoswitchable Menthol

Becker, Jasmin, Ellerkmann, Clara S., Schmelzer, Hannah, Hermann, Christian, Lützel, Kyra, Gudermann, Thomas, Konrad, David B., Trauner, Dirk, Storch, Ursula and Mederos y Schnitzler, Michael (2024) Optical Control of TRPM8 Channels with Photoswitchable Menthol. Angewandte Chemie International Edition.

Date of publication of this fulltext: 07 Jan 2025 10:32
Article
DOI to cite this document: 10.5283/epub.74555


Abstract

Transient receptor potential melastatin 8 (TRPM8) channels are well known as sensors for cold temperatures and cooling agents such as menthol and icilin and these channels are tightly regulated by the membrane lipid phosphoinositol-4,5-bisphosphate (PIP2). Since TRPM8 channels emerged as promising drug targets for treating pain, itching, obesity, cancer, dry eye disease, and inflammation, we ...

Transient receptor potential melastatin 8 (TRPM8) channels are well known as sensors for cold temperatures and cooling agents such as menthol and icilin and these channels are tightly regulated by the membrane lipid phosphoinositol-4,5-bisphosphate (PIP2). Since TRPM8 channels emerged as promising drug targets for treating pain, itching, obesity, cancer, dry eye disease, and inflammation, we aimed at developing a high-precision TRPM8 channel activator, to achieve spatiotemporal control of TRPM8 activity with light. In this study, we designed, synthesized and characterized the first photoswitchable TRPM8 activator azo-menthol (AzoM). AzoM enables optical control of endogenously and heterologously expressed TRPM8 channels with UV and blue light which is demonstrated by performing patch-clamp experiments. Moreover, AzoM facilitates the reliable determination of activation, inactivation, and deactivation kinetics thereby providing further insights into the channel gating. Using AzoM, the specific roles of individual amino acids for AzoM or PIP2 binding and for sensitization by PIP2 can be elucidated. Altogether, AzoM represents as a high-precision pharmaceutical tool for reversible control of TRPM8 channel function that enhances our biophysical understanding of TRPM8 channels and holds the potential to support the development of novel pharmaceuticals.



Involved Institutions


Details

Item typeArticle
Journal or Publication TitleAngewandte Chemie International Edition
Publisher:Wiley
Open Access Type:DEAL (Wiley)
Date11 December 2024
InstitutionsChemistry and Pharmacy > Institute of Pharmacy
Identification Number
ValueType
10.1002/anie.202416549DOI
Keywordsphotopharmacology · ion channels · TRPM8 · photoswitchable menthol · current kinetics ms an
Dewey Decimal Classification600 Technology > 615 Pharmacy
StatusPublished
RefereedYes, this version has been refereed
Created at the University of RegensburgPartially
URN of the UB Regensburgurn:nbn:de:bvb:355-epub-745551
Item ID74555

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