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Structural landscape of activation, desensitization and inhibition in the human TRPM4 channel

Celso M Teixeira-Duarte1,2, Weizhong Zeng1,2, Youxing Jiang3,4

  • 1Howard Hughes Medical Institute and Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Nature Structural & Molecular Biology
|November 1, 2025
PubMed

Insights

Transient Receptor Potential Melastatin 4 (TRPM4) channels are crucial for cellular signaling. This study reveals the molecular mechanisms of TRPM4 activation, desensitization, and inhibition using cryo-EM structures.

Area of Science:

  • Molecular biology
  • Cellular physiology
  • Structural biology

Background:

  • TRPM4 is a Ca2+-activated cation channel involved in diverse cellular processes.
  • Its activity is modulated by intracellular Ca2+, ATP, and PtdIns(4,5)P2 levels.
  • Understanding TRPM4 function is key to deciphering various signaling pathways.

Purpose of the Study:

  • To elucidate the molecular mechanisms of TRPM4 channel gating.
  • To provide structural insights into TRPM4 activation, desensitization, and inhibition.
  • To establish a structural foundation for understanding TRPM4's physiological roles.

Main Methods:

  • Single-particle cryo-electron microscopy (cryo-EM) of human TRPM4.
  • Mutagenesis studies.
  • Electrophysiological analyses.

Main Results:

  • Four distinct cryo-EM structures of human TRPM4 were determined: apo closed, Ca2+-bound desensitized, Ca2+-PtdIns(4,5)P2-bound open, and ATP-bound inhibited.
  • These structures reveal conformational changes associated with channel gating.
  • The findings elucidate how cellular signaling molecules regulate TRPM4 activity.

Conclusions:

  • The study provides unprecedented structural detail of TRPM4 in multiple functional states.
  • These insights explain how TRPM4 integrates signals from Ca2+, ATP, and PtdIns(4,5)P2.
  • This work offers a structural basis for future research into TRPM4-mediated physiology and disease.

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