权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cellular Physiology of Otopetrin Proton Channels

奥托布林质子通道的细胞生理学

基本信息

批准号：
10373969
负责人：
EMILY R. LIMAN
金额：
$ 35.48万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373969
关键词：
Acceleration Address Adipose tissue Alkalinization Amino Acids Architecture Binding Sites Biophysics Brown Fat Calcium Carbonate Cell membrane Cell physiology Cells Chemosensitization Collaborations Cryoelectron Microscopy Cysteine Data Dependence Development Disease Electrophysiology (science)Elements Eukaryotic Cell Exposure to Family Funding Gastrointestinal tract structure Gene Family Gravitation Hair Cells Immune Immune system Inherited Ion Channel Ions Kinetics Mediating Mouse Strains Mus Mutation Pathway interactions Permeability Pharmacologic Substance Physiological Point Mutation Property Protein Isoforms Protons Publishing Reagent Series Site-Directed Mutagenesis Stimulus Structure Synaptic Vesicles System Taste Perception Testing Transcript Xenopus oocyte base experimental study extracellular gastrointestinal system insight mammalian genome member otoconia patch clamp response structural biology voltage ward

项目摘要

PROJECT SUMMARY/ABSTRACT The proposed experiments are aimed at elucidating the structural and functional properties of a newly discovered family of ion channels, the Otopetrins (Otops). The Otops are just the second class, after Hv1, of proton-selective ion channels described in eukaryotic cells. Otop1 was first discovered in the vestibular system where it is required for the development of calcium carbonate-based otoconia that allow hair cells to detect changes in gravitational forces and acceleration. It was subsequently identified in an unbiased screen for proton channels based on functional analysis of transcripts enriched in taste cells that detect sour. When expressed in Xenopus oocytes and HEK- 293 cells, Otop1 generates a proton-selective ion current that is blocked by extracellular Zn[2+]. The mammalian genome encodes two homologs of Otop1 (Otop2 and Otop3), which also form proton permeable ion channels with distinct functional properties. Here we propose a series of experiments to define mechanisms of gating and permeation of Otop channels, and to identify the underlying structural elements. The CryoEm structure of Otop1 and Otop3 have led us to identify several possible proton permeation pathways; the function of specific residues in permeation or Zn[2+] inhibition will be interrogated using site directed mutagenesis and patch clamp electrophysiology. Other experiments will address the outstanding question of whether Otop channels are gated and identify structural determinants for gating. Members of the otopetrin gene family are widely expressed throughout the body, including in the taste, vestibular and immune systems, in the gastrointestinal tract, and in brown adipose tissue. By understanding the structural and functional properties of each of the Otop isoforms, we will be better able to understand how they contributes to cellular physiology. Moreover, ion channels are the preferred targets for pharmaceuticals and mutations that disrupt their function underlie a growing number of inherited or acquired disorders (channelopathies).

项目总结/文摘