Liu Dan, Liman Emily R
Department of Biological Sciences and Program in Neuroscience, University of Southern California, Los Angeles, CA 90089, USA.
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15160-5. doi: 10.1073/pnas.2334159100. Epub 2003 Dec 1.
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.
味觉转导是一个基本过程，它使动物能够区分营养物质和有害物质。苦味、甜味和氨基酸这三种味觉模式由G蛋白偶联受体介导，这些受体通过一个共同的转导级联发出信号：磷脂酶Cβ2的激活，导致磷脂酰肌醇-4,5-二磷酸（PIP2）分解为二酰甘油和肌醇1,4,5-三磷酸，进而引起细胞内储存的Ca2+释放。离子通道TRPM5是这个级联反应的一个重要组成部分；然而，其激活机制尚不清楚。在这里，我们表明，异源表达的TRPM5形成一个阳离子通道，该通道直接被微摩尔浓度的细胞内Ca2+激活（半最大激活浓度K1/2 = 21微摩尔）。持续暴露于Ca2+会使TRPM5通道脱敏，但PIP2可逆转脱敏，部分恢复通道活性。全细胞TRPM5电流可被细胞内Ca2+激活，并且由于通道的电压敏感门控而表现出强烈的外向整流。TRPM5通道对单价阳离子无选择性，对二价阳离子无明显通透性。我们提出，Ca2+对TRPM5的调节介导了味觉系统中的感觉激活。
