Members of the voltage-gated superfamily of ion channels generate the action potential and govern neural excitability, muscle contraction, neurotransmitter release and visual and olfactory signal transduction. These channels include voltage-gated K+, Na+, and Ca++ channels, as well as channels gated by cytoplasmic ligands such as Ca++ and cyclic nucleotides. As a group these channels are capable of high flux rate, but range in ion selectivity, though they all exclude anions. The channels appear to have a similar overall structure and may well gate by similar means. Understanding the operational principles of any one of the members should provide important insights into how they all function. This understanding should help in the development of new therapies which target specific channels in the superfamily for treatment of diseases as various as cardiovascular disease, intractable pain, and myotonia. This proposal sets out to define how voltage-gated ion channels respond to changes in membrane potential by opening and closing their molecular gates. The gates control access of permeant ions to the pore (and thus transmembrane ion flux) at several different locations along the length of the pore. The precise locations, structures, and rearrangements of the voltage sensors and gates of these channels are, at best, only partly understood. Also not well understood are the mechanisms by which voltage sensors in each of a channel's four subunits act to open or close the channel gates. The goal of this proposal is to further our understanding of these issues and to obtain a structural map of the Shaker K+ channel in various functional states. The long- term goal is to reconstruct in four dimensions the protein motions that underlie voltage sensing, that open and close the channel gates, and that couple the voltage-sensing apparatus to the gates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035549-08
Application #
6639509
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (03))
Program Officer
Stewart, Randall
Project Start
1996-09-15
Project End
2004-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
8
Fiscal Year
2003
Total Cost
$370,253
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Palty, Raz; Fu, Zhu; Isacoff, Ehud Y (2017) Sequential Steps of CRAC Channel Activation. Cell Rep 19:1929-1939
Chen, Yushu; Bharill, Shashank; Altun, Zeynep et al. (2016) Caenorhabditis elegans paraoxonase-like proteins control the functional expression of DEG/ENaC mechanosensory proteins. Mol Biol Cell 27:1272-85
Chen, Yushu; Bharill, Shashank; O'Hagan, Robert et al. (2016) MEC-10 and MEC-19 Reduce the Neurotoxicity of the MEC-4(d) DEG/ENaC Channel in Caenorhabditis elegans. G3 (Bethesda) 6:1121-30
Palty, Raz; Isacoff, Ehud Y (2016) Cooperative Binding of Stromal Interaction Molecule 1 (STIM1) to the N and C Termini of Calcium Release-activated Calcium Modulator 1 (Orai1). J Biol Chem 291:334-41
Levitz, Joshua; Royal, Perrine; Comoglio, Yannick et al. (2016) Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels. Proc Natl Acad Sci U S A 113:4194-9
Berger, Thomas K; Isacoff, Ehud Y (2015) Fluorescent labeling for patch-clamp fluorometry (PCF) measurements of real-time protein motion in ion channels. Methods Mol Biol 1266:93-106
Palty, Raz; Stanley, Cherise; Isacoff, Ehud Y (2015) Critical role for Orai1 C-terminal domain and TM4 in CRAC channel gating. Cell Res 25:963-80
Chen, Yushu; Bharill, Shashank; Isacoff, Ehud Y et al. (2015) Subunit composition of a DEG/ENaC mechanosensory channel of Caenorhabditis elegans. Proc Natl Acad Sci U S A 112:11690-5
Mony, Laetitia; Berger, Thomas K; Isacoff, Ehud Y (2015) A specialized molecular motion opens the Hv1 voltage-gated proton channel. Nat Struct Mol Biol 22:283-290
Comoglio, Yannick; Levitz, Joshua; Kienzler, Michael A et al. (2014) Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid. Proc Natl Acad Sci U S A 111:13547-52

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