Decavanadate modulates gating of TRPM4 cation channels. Export

@article{citeulike:1292091, abstract = {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.}, address = {Department of Physiology, Campus Gasthuisberg, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium. bernd.nilius@med.kuleuven.ac.be}, author = {Nilius, B. and Prenen, J. and Janssens, A. and Voets, T. and Droogmans, G.}, citeulike-article-id = {1292091}, citeulike-linkout-0 = {http://dx.doi.org/10.1113/jphysiol.2004.070839}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/15331675}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=15331675}, doi = {10.1113/jphysiol.2004.070839}, issn = {0022-3751}, journal = {J Physiol}, keywords = {cation, channel, medsci733, non, selective, trpm4}, month = {November}, number = {Pt 3}, pages = {753--765}, posted-at = {2007-05-13 05:46:32}, priority = {2}, title = {Decavanadate modulates gating of TRPM4 cation channels.}, url = {http://dx.doi.org/10.1113/jphysiol.2004.070839}, volume = {560}, year = {2004} }

TY - JOUR ID - citeulike:1292091 L3 - citeulike-article-id:1292091 N2 - 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. IS - Pt 3 JF - J Physiol SN - 0022-3751 AD - Department of Physiology, Campus Gasthuisberg, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium. bernd.nilius@med.kuleuven.ac.be EP - 765 TI - Decavanadate modulates gating of TRPM4 cation channels. VL - 560 SP - 753 KW - cation KW - channel KW - medsci733 KW - non KW - selective KW - trpm4 AU - Nilius, B AU - Prenen, J AU - Janssens, A AU - Voets, T AU - Droogmans, G PY - 2004/11/01/ UR - http://dx.doi.org/10.1113/jphysiol.2004.070839 ER -