Decavanadate modulates gating of TRPM4 cation channels

J Physiol. 2004 Nov 1;560(Pt 3):753-65. doi: 10.1113/jphysiol.2004.070839. Epub 2004 Aug 26.


We have tested the effects of decavanadate (DV), a compound known to interfere with ATP binding in ATP-dependent transport proteins, on TRPM4, a Ca(2+)-activated, voltage-dependent monovalent cation channel, whose activity is potently blocked by intracellular ATP(4-). Application of micromolar Ca(2+) concentrations to the cytoplasmic side of inside-out patches led to immediate current activation followed by rapid current decay, which can be explained by an at least 30-fold decreased apparent affinity for Ca(2+). Subsequent application of DV (10 microm) strongly affected the voltage-dependent gating of the channel, resulting in large sustained currents over the voltage range between -180 and +140 mV. The effect of DV was half-maximal at a concentration of 1.9 microm. The Ca(2+)- and voltage-dependent gating of the channel was well described by a sequential kinetic scheme in which Ca(2+) binding precedes voltage-dependent gating. The effects of DV could be explained by an action on the voltage-dependent closing step. Surprisingly, DV did not antagonize the effect of ATP(4-) on TRPM4, but caused a nearly 10-fold increase in the sensitivity of the ATP(4-) block. TRPM5, which is the most homologous channel to TRPM4, was not modulated by DV. The effect of DV was lost in a TRPM4 chimera in which the C-terminus was substituted with that of TRPM5. Deletion of a cluster in the C-terminus of TRPM4 containing positively charged amino acid residues with a high homology to part of the decavanadate binding site in SERCA pumps, completely abolished the DV effect but also accelerated desensitization. Deletion of a similar site in the N-terminus had no effects on DV responses. These results indicate that the C-terminus of TRPM4 is critically involved in mediating the DV effects. In conclusion, decavanadate modulates TRPM4, but not TRPM5, by inhibiting voltage-dependent closure of the channel.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Animals
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels / physiology*
  • Cation Transport Proteins / antagonists & inhibitors
  • Cation Transport Proteins / physiology*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Humans
  • Ion Channel Gating / drug effects*
  • Ion Channel Gating / physiology
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology
  • Mice
  • TRPM Cation Channels
  • Vanadates / pharmacology*


  • Calcium Channel Blockers
  • Calcium Channels
  • Cation Transport Proteins
  • Membrane Proteins
  • TRPM Cation Channels
  • TRPM4 protein, human
  • TRPM5 protein, human
  • Trpm5 protein, mouse
  • Vanadates
  • Adenosine Triphosphate