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      BK channels: multiple sensors, one activation gate

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          Abstract

          Ion transport across cell membranes is essential to cell communication and signaling. Passive ion transport is mediated by ion channels, membrane proteins that create ion conducting pores across cell membrane to allow ion flux down electrochemical gradient. Under physiological conditions, majority of ion channel pores are not constitutively open. Instead, structural region(s) within these pores breaks the continuity of the aqueous ion pathway, thereby serves as activation gate(s) to control ions flow in and out. To achieve spatially and temporally regulated ion flux in cells, many ion channels have evolved sensors to detect various environmental stimuli or the metabolic states of the cell and trigger global conformational changes, thereby dynamically operate the opening and closing of their activation gate. The sensors of ion channels can be broadly categorized as chemical sensors and physical sensors to respond to chemical (such as neural transmitters, nucleotides and ions) and physical (such as voltage, mechanical force and temperature) signals, respectively. With the rapidly growing structural and functional information of different types of ion channels, it is now critical to understand how ion channel sensors dynamically control their gates at molecular and atomic level. The voltage and Ca 2+ activated BK channels, a K + channel with an electrical sensor and multiple chemical sensors, provide a unique model system for us to understand how physical and chemical energy synergistically operate its activation gate.

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          Most cited references172

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          Voltage sensor of Kv1.2: structural basis of electromechanical coupling.

          Voltage-dependent ion channels contain voltage sensors that allow them to switch between nonconductive and conductive states over the narrow range of a few hundredths of a volt. We investigated the mechanism by which these channels sense cell membrane voltage by determining the x-ray crystal structure of a mammalian Shaker family potassium ion (K+) channel. The voltage-dependent K+ channel Kv1.2 grew three-dimensional crystals, with an internal arrangement that left the voltage sensors in an apparently native conformation, allowing us to reach three important conclusions. First, the voltage sensors are essentially independent domains inside the membrane. Second, they perform mechanical work on the pore through the S4-S5 linker helices, which are positioned to constrict or dilate the S6 inner helices of the pore. Third, in the open conformation, two of the four conserved Arg residues on S4 are on a lipid-facing surface and two are buried in the voltage sensor. The structure offers a simple picture of how membrane voltage influences the open probability of the channel.
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            Crystal structure and mechanism of a calcium-gated potassium channel.

            Ion channels exhibit two essential biophysical properties; that is, selective ion conduction, and the ability to gate-open in response to an appropriate stimulus. Two general categories of ion channel gating are defined by the initiating stimulus: ligand binding (neurotransmitter- or second-messenger-gated channels) or membrane voltage (voltage-gated channels). Here we present the structural basis of ligand gating in a K(+) channel that opens in response to intracellular Ca(2+). We have cloned, expressed, analysed electrical properties, and determined the crystal structure of a K(+) channel (MthK) from Methanobacterium thermoautotrophicum in the Ca(2+)-bound, opened state. Eight RCK domains (regulators of K(+) conductance) form a gating ring at the intracellular membrane surface. The gating ring uses the free energy of Ca(2+) binding in a simple manner to perform mechanical work to open the pore.
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              Contribution of the S4 segment to gating charge in the Shaker K+ channel.

              Voltage-activated ion channels respond to changes in membrane voltage by coupling the movement of charges to channel opening. A K+ channel-specific radioligand was designed and used to determine the origin of these gating charges in the Shaker K+ channel. Opening of a Shaker K+ channel is associated with a displacement of 13.6 electron charge units. Gating charge contributions were determined for six of the seven positive charges in the S4 segment, an unusual amino acid sequence in voltage-activated cation channels consisting of repeating basic residues at every third position. Charge-neutralizing mutations of the first four positive charges led to large decreases (approximately 4 electron charge units each) in the gating charge; however, the gating charge of Shaker delta 10, a Shaker K+ channel with 10 altered nonbasic residues in its S4 segment, was found to be identical to the wild-type channel. These findings show that movement of the NH2-terminal half but not the CO2H-terminal end of the S4 segment underlies gating charge, and that this portion of the S4 segment appears to move across the entire transmembrane voltage difference in association with channel activation.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                06 February 2015
                2015
                : 6
                : 29
                Affiliations
                [1] 1Ion Channel Research Unit, Duke University Medical Center Durham, NC, USA
                [2] 2Department of Biochemistry, Duke University Medical Center Durham, NC, USA
                [3] 3Department of Biomedical Engineering, Washington University in Saint Louis St. Louis, MO, USA
                [4] 4Cardiac Bioelectricity and Arrhythmia Center, Washington University in Saint Louis St. Louis, MO, USA
                [5] 5Center for The Investigation of Membrane Excitability Disorders, Washington University in Saint Louis St. Louis, MO, USA
                Author notes

                Edited by: Alex M. Dopico, The University of Tennessee Health Science Center, USA

                Reviewed by: Brad S. Rothberg, Temple University School of Medicine, USA; Karl L. Magleby, University of Miami, USA

                *Correspondence: Jianmin Cui, Department of Biomedical Engineering, Washington University, 1 Brookings Drive, Whitaker Hall, Room 290C, St. Louis, MO 63130, USA e-mail: jcui@ 123456wustl.edu

                This article was submitted to Membrane Physiology and Membrane Biophysics, a section of the journal Frontiers in Physiology.

                Article
                10.3389/fphys.2015.00029
                4319557
                25705194
                827d59de-9040-4709-9ebd-89552c70d8d4
                Copyright © 2015 Yang, Zhang and Cui.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 January 2015
                : 19 January 2015
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 205, Pages: 16, Words: 15582
                Categories
                Physiology
                Review Article

                Anatomy & Physiology
                bk channels,allosteric gating,calcium binding proteins,modular organization,ion permeation,voltage sensor domain,magnesium binding,ion channel gating

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