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The selectivity filter of the cation channel TRPM4
Bernd Nilius1, Jean Prenen, Annelies Janssens
1Department of Physiology, Campus Gasthuisberg, KU Leuven, Belgium. bernd.nilius@med.kuleuven.ac.be
The Journal of Biological Chemistry
|April 23, 2005
Summary
Researchers identified the selectivity filter in Transient Receptor Potential Melastatin (TRPM) 4 channels, revealing structural elements responsible for their unique Ca(2+)-impermeability. This finding offers insights into TRPM channel function and cation selectivity.
Area of Science:
- Molecular Biology
- Biophysics
- Ion Channel Physiology
Background:
- Transient receptor potential channel melastatin subfamily (TRPM) 4 and TRPM5 are unique cation channels impermeable to Ca(2+).
- Understanding the structural basis of TRPM4's Ca(2+) impermeability is crucial for elucidating its physiological roles.
Purpose of the Study:
- To locate the TRPM4 selectivity filter.
- To investigate structural elements conferring Ca(2+) impermeability to TRPM4.
- To understand the molecular basis of TRPM channel monovalent cation selectivity.
Main Methods:
- Homology modeling to identify potential selectivity filter regions.
- Site-directed mutagenesis of the putative TRPM4 selectivity filter.
- Functional characterization of mutant TRPM4 channels using electrophysiology and cation flux assays.
Main Results:
- An acidic amino acid stretch (EDMDVA) in the TM5-TM6 loop was identified as the TRPM4 selectivity filter.
- Substitution with TRPV6 selectivity filter conferred Ca(2+) permeability and altered ion block properties.
- Mutations within the TRPM4 selectivity filter affected channel function, ion permeability, and voltage dependence.
Conclusions:
- The study delineates the selectivity filter of TRPM channels.
- Key acidic residues within the selectivity filter are critical for TRPM4's Ca(2+) impermeability and ion permeation properties.
- These findings provide the first molecular insights into TRPM channel monovalent cation selectivity.