Electron cryo-microscopy structure of a human TRPM4 channel

Area of Science:

• Molecular Biology
• Biophysics
• Structural Biology

Background:

• Calcium-activated non-selective (CAN) ion channels regulate cellular calcium entry.
• These channels are vital for neuronal bursting and cardiac rhythm.
• TRPM4 is a widespread and important member of the CAN channel family.

Purpose of the Study:

• To determine the structure of the human TRPM4 channel.
• To understand the binding of calcium (Ca2+) and decavanadate to TRPM4.
• To elucidate the functional and pharmacological properties of CAN and TRPM channels.

Main Methods:

• Electron cryo-microscopy (cryo-EM) was used to visualize the TRPM4 channel structure.
• The structure was determined in the presence of the agonist Ca2+ and the modulator decavanadate.

Main Results:

• The structure reveals a crown-like architecture of four TRPM4 subunits.
• Cytosolic C-terminal domains form an umbrella-like structure.
• Two decavanadate-binding sites were identified, one in the C-terminal domain and another at the intersubunit MHR interface.
• A glutamine residue in the selectivity filter may determine monovalent ion selectivity.

Conclusions:

• The determined structure offers novel insights into TRPM4 channel function.
• This structural information can advance the understanding of CAN and TRPM channel families.
• The findings may guide future pharmacological targeting of these ion channels.