Molecular physiology of CALHM ion channels

CALHM 离子通道的分子生理学

• 批准号: 10647746
• 负责人: James Kevin FOSKETT
• 金额: $ 57.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647746
• 关键词: Action Potentials; Address; Affect; Brain; Central Nervous System; Charge; Cryoelectron Microscopy; Dependence; Diabetes Mellitus; Diameter; Electrophysiology (science); Elements; Engineering; Esthesia; Evoked Potentials; Family; Food; Formulation; G-Protein-Coupled Receptors; Genetic; Goals; Homologous Gene; Human; Ion Channel; Ions; Kinetics; Knockout Mice; Life; Mediating; Medicine; Membrane Proteins; Methods; Modeling; Molecular; Mus; Mutagenesis; Nerve; Neurons; Neurotransmitters; Nutritional; Obesity; Pathway interactions; Perception; Peripheral; Permeability; Physiological; Physiology; Play; Proteins; Regulation; Role; Scheme; Signal Transduction; Structure; System; TRPM5 gene; Taste Bud Cell; Taste Buds; Taste Perception; Temperature; Type II Epithelial Receptor Cell; base; extracellular; insight; mouse model; mutant; neurotransmitter release; novel; pharmacologic; response; taste system; taste transduction; voltage

The broad goal of our proposed studies is to exploit our new insights into the molecular mechanisms and physiological roles of CALHM1 and CALHM3 as components of a novel ion channel in taste perception. We discovered CALHM1 as a membrane protein that expressed throughout the brain and in taste buds that lacks significant homology to other proteins, although five homologs have been identified, and CALHM1 is conserved across species. We identified CALHM1 as a pore-forming subunit of an ion channel with a large pore diameter and gating regulation by voltage and extracellular Ca2+ (Ca2+o). We discovered that CALHM1 is essential for perceptions of sweet, bitter and umami tastes by type II taste bud cells, since CALHM1-knockout mice cannot perceive these tastants. We identified the essential role of CALHM1 by discovering that it is a voltage-gated ATP-permeable ion channel, and that tastant-evoked Na+ action potentials trigger ATP release as a neurotransmitter through CALHM1-associated channels to transduce taste information from the periphery to the central nervous system. We further discovered that CALHM3 is an essential component of the native voltage-gated ATP-release channel, contributing as a pore-forming subunit with CALHM1 to create a heteromeric ATP-release channel in type II cells. Genetic deletion of CALHM3 also eliminates the ability of mice to perceive sweet, bitter and umami substances. The molecular mechanisms and structural bases of ion permeation and gating of CALHM channels are not understood despite their physiological importance. Nor is it understood how integration of CALHM3 into a CALHM1/3 channel so strongly affects voltage-gated activation, a key feature that allows CALHM1/3 channels to respond to action potentials. Temperature notably influences taste perception with physiological and hedonistic implications, but the contribution of peripheral taste-transduction mechanisms to the effects of temperature on the perception and sensation of tastes is largely unknown. We have discovered that temperature strikingly influences CALHM1/3 conductance as well as the electrical excitability of type II cells. We will employ electrophysiology in native taste bud cells and heterologous expression systems, mutagenesis, cryo-EM, and modeling to define the gating mechanisms of CALHM1 and CALHM1/3 channels, how CALHM3 as a pore-forming subunit enhances voltage-gated activation of CALHM1/3 channels, and how CALHM1/3 channels respond to action potentials evoked by tastant stimulation over a wide range of temperatures. Using a novel mouse model in which CALHM1/3 in taste bud cells has been engineered to have distinct temperature sensitivity, we will define how differential effects of temperature on ATP-release channel gating and excitability may provide a mechanism for how a temperature-sensitive channel in the peripheral gustatory system contributes to the influence of temperature on taste sensitivity and perception.

我们提出的研究的广泛目标是利用我们对分子机制和

项目成果

Taste transduction and channel synapses in taste buds.

• DOI: 10.1007/s00424-020-02464-4
• 发表时间: 2021-01
• 期刊: PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
• 影响因子: 4.5
• 作者: Taruno, Akiyuki;Nomura, Kengo;Kusakizako, Tsukasa;Ma, Zhongming;Nureki, Osamu;Foskett, J. Kevin
• 通讯作者: Foskett, J. Kevin

Acute Regulation of Habituation Learning via Posttranslational Palmitoylation.

• DOI: 10.1016/j.cub.2020.05.016
• 发表时间: 2020-07-20
• 期刊: Current biology : CB
• 作者: Nelson JC;Witze E;Ma Z;Ciocco F;Frerotte A;Randlett O;Foskett JK;Granato M
• 通讯作者: Granato M