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Optical Control of TRPM8 Channels with Photoswitchable Menthol

Jasmin Becker1, Clara S Ellerkmann1, Hannah Schmelzer1

  • 1Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Goethestr. 33, 80336, Munich, Germany.

Angewandte Chemie (International Ed. in English)
|December 11, 2024
PubMed

Insights

Researchers developed azo-menthol (AzoM), the first photoswitchable activator for Transient Receptor Potential Melastatin 8 (TRPM8) channels. This tool allows precise optical control of TRPM8 activity, aiding drug development for pain and other conditions.

Area of Science:

  • Biophysics
  • Pharmacology
  • Molecular Biology

Background:

  • Transient receptor potential melastatin 8 (TRPM8) channels are key sensors for cold and menthol.
  • TRPM8 channels are regulated by phosphoinositol-4,5-bisphosphate (PIP2) and are therapeutic targets for pain, inflammation, and other diseases.

Purpose of the Study:

  • To develop a light-controlled activator for precise spatiotemporal manipulation of TRPM8 channel activity.
  • To create a novel pharmaceutical tool for studying TRPM8 channel gating and drug interactions.

Main Methods:

  • Design, synthesis, and characterization of azo-menthol (AzoM), a photoswitchable TRPM8 activator.
  • Patch-clamp electrophysiology to demonstrate light-induced TRPM8 channel activation and kinetics.
  • Investigation of AzoM and PIP2 interactions with TRPM8 channel amino acids.

Main Results:

  • AzoM provides precise optical control (UV and blue light) over endogenous and heterologous TRPM8 channels.
  • AzoM enables accurate determination of TRPM8 channel activation, inactivation, and deactivation kinetics.
  • The study elucidates the roles of specific amino acids in AzoM/PIP2 binding and PIP2-dependent sensitization.

Conclusions:

  • AzoM is a high-precision tool for reversible control of TRPM8 channel function.
  • This photoswitchable activator enhances biophysical understanding of TRPM8 channels.
  • AzoM holds potential for developing novel therapeutics targeting TRPM8-related conditions.
Keywords:
TRPM8current kineticsion channelsphotopharmacologyphotoswitchable menthol

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