title: Intracellular Ca2+ and the phospholipid PIP2 regulate the taste transduction ion channel TRPM5.
abstract: The transduction of taste is a fundamental process that allows animals to discriminate nutritious from noxious substances. Three taste modalities, bitter, sweet, and amino acid, are mediated by G protein-coupled receptors that signal through a common transduction cascade: activation of phospholipase C beta2, leading to a breakdown of phosphatidylinositol-4,5-bisphosphate (PIP2) into diacylglycerol and inositol 1,4,5-trisphosphate, which causes release of Ca2+ from intracellular stores. The ion channel, TRPM5, is an essential component of this cascade; however, the mechanism by which it is activated is not known. Here we show that heterologously expressed TRPM5 forms a cation channel that is directly activated by micromolar concentrations of intracellular Ca2+ (K1/2 = 21 microM). Sustained exposure to Ca2+ desensitizes TRPM5 channels, but PIP2 reverses desensitization, partially restoring channel activity. Whole-cell TRPM5 currents can be activated by intracellular Ca2+ and show strong outward rectification because of voltage-sensitive gating of the channels. TRPM5 channels are nonselective among monovalent cations and not detectably permeable to divalent cations. We propose that the regulation of TRPM5 by Ca2+ mediates sensory activation in the taste system.
authors.affiliation: Department of Biological Sciences and Program in Neuroscience, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Emily R
authors.initials: ER
authors.lastname: Liman
mesh_terms: D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D002412:Cations; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004594:Electrophysiology; D004789:Enzyme Activation; D017353:Gene Deletion; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry* / Q000378:metabolism; D054799:Phospholipase C beta; D015398:Signal Transduction; D050053:TRPM Cation Channels; D013649:Taste; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D002412:Cations; D018076:DNA, Complementary; D007476:Ionophores; D007527:Isoenzymes; D008565:Membrane Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D050053:TRPM Cation Channels; C404409:TRPM5 protein, human; C498617:Trpm5 protein, mouse; D010738:Type C Phospholipases; C518036:PLCB2 protein, human; D054799:Phospholipase C beta; C518037:Plcb2 protein, mouse; D002118:Calcium