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Decavanadate modulates gating of TRPM4 cation channels
Bernd Nilius1, Jean Prenen, Annelies Janssens
1Department of Physiology, Campus Gasthuisberg, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium. bernd.nilius@med.kuleuven.ac.be
The Journal of Physiology
|August 28, 2004
Summary
Decavanadate (DV) modulates the TRPM4 channel by inhibiting voltage-dependent closure, enhancing ATP sensitivity. This effect is specific to TRPM4 and mediated by its C-terminus, not observed in TRPM5.
Area of Science:
- Molecular Biology
- Ion Channel Physiology
- Biochemistry
Background:
- TRPM4 is a Ca(2+)-activated, voltage-dependent monovalent cation channel.
- Intracellular ATP(4-) potently blocks TRPM4 activity.
- Decavanadate (DV) is known to interfere with ATP binding in transport proteins.
Purpose of the Study:
- To investigate the effects of decavanadate (DV) on the TRPM4 ion channel.
- To elucidate the mechanism by which DV modulates TRPM4 activity and gating.
- To identify the regions of TRPM4 responsible for DV interaction.
Main Methods:
- Electrophysiological recordings (inside-out patches) to measure TRPM4 currents.
- Application of varying concentrations of Ca(2+) and DV.
- Site-directed mutagenesis (chimeras and deletions) to probe functional domains.
Main Results:
- DV (1.9 µM EC50) strongly affected TRPM4 voltage-dependent gating, causing sustained currents.
- DV increased TRPM4 sensitivity to ATP(4-) block, rather than antagonizing it.
- DV's effects were specific to TRPM4, absent in TRPM5, and localized to TRPM4's C-terminus.
Conclusions:
- Decavanadate modulates TRPM4 channel activity by inhibiting voltage-dependent closure.
- The C-terminus of TRPM4 is critical for mediating decavanadate's effects.
- Decavanadate enhances the inhibitory effect of ATP on TRPM4.