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Updated: Nov 7, 2025

Yeast Luminometric and Xenopus Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4
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Species-Specific Regulation of TRPM2 by PI(4,5)P2 via the Membrane Interfacial Cavity

Daniel Barth1, Andreas Lückhoff1, Frank J P Kühn1

  • 1Institute of Physiology, Medical Faculty, RWTH Aachen University Hospital, D52057 Aachen, Germany.

International Journal of Molecular Sciences
|April 30, 2021
PubMed

Insights

Phosphatidylinositol 4,5-bisphosphate (PIP2) is crucial for activating TRPM2 channels across species. Human TRPM2 shows unique sensitivity to PIP2 levels, impacting channel regulation.

Area of Science:

  • Ion channel physiology
  • Molecular biology
  • Biochemistry

Background:

  • The apoptosis channel TRPM2 is activated by ADPR and Ca2+.
  • Species-specific activation mechanisms for TRPM2 have been observed.
  • The role of phosphatidylinositol 4,5-bisphosphate (PIP2) in TRPM2 function is not fully understood.

Purpose of the Study:

  • To investigate the functional effect of PIP2 on different TRPM2 orthologues.
  • To identify the specific interaction site between TRPM2 and PIP2.
  • To understand the species-specific regulation of TRPM2 by PIP2.

Main Methods:

  • Utilized inside-out patch clamp recordings in HEK-293 cells expressing TRPM2 orthologues.
  • Manipulated PIP2 levels by depletion (polylysine) and restoration (artificial PIP2).
  • Introduced mutations in conserved residues within the membrane interfacial cavity of TRPM2.

Main Results:

  • PIP2 plays a critical role in activating TRPM2 orthologues from humans, zebrafish, and sea anemones.
  • TRPM2 orthologues exhibited varied responses to PIP2 restoration, with human TRPM2 being least sensitive.
  • Mutations in conserved residues of the membrane interfacial cavity reduced PIP2 sensitivity across all tested orthologues.
  • Depletion of PIP2 uniformly inactivated TRPM2 channels.

Conclusions:

  • The membrane interfacial cavity serves as a conserved PIP2 binding site for TRPM2.
  • PIP2 binding facilitates TRPM2 activation by ADPR and Ca2+ in a species-specific manner.
  • Human TRPM2's lower sensitivity to PIP2 suggests enhanced regulation by endogenous PIP2 levels.
Keywords:
PIP2TRPM2patch clampphosphoinositidesphospholipid

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