Cryo-EM structure of TRPC5 at 2.8-Å resolution reveals unique and conserved structural elements essential for channel...

Area of Science:

• Structural biology
• Ion channel biophysics
• Molecular pharmacology

Background:

• Transient receptor potential canonical subfamily member 5 (TRPC5) is a calcium-permeant cation channel.
• TRPC5 is a significant drug target for progressive kidney disease, depression, and anxiety.
• Understanding TRPC5 structure is crucial for developing targeted therapeutics.

Purpose of the Study:

• To determine the high-resolution structure of the mouse TRPC5 (mTRPC5) homotetramer.
• To identify structural differences between TRPC5 and other TRP channels.
• To elucidate the mechanisms of lipid modulation and gating in TRPC channels.

Main Methods:

• Cryo-electron microscopy (cryo-EM) at 2.8-Å resolution
• Electrophysiology
• Site-directed mutagenesis

Main Results:

• The 2.8-Å resolution cryo-EM structure of the mTRPC5 homotetramer was determined.
• Structural comparisons revealed distinct extracellular pore domain features and S3 helix lengths in TRPC5.
• A disulfide bond and adjacent loop on the extracellular pore are critical for mTRPC5 function.

Conclusions:

• The high-resolution mTRPC5 structure offers critical insights into ion channel architecture.
• Structural findings illuminate TRPC5's role in lipid modulation and gating mechanisms.
• This work provides a foundation for TRPC5-targeted drug development.