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      Voltage Sensor Inactivation in Potassium Channels

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          Abstract

          In voltage-gated potassium (Kv) channels membrane depolarization causes movement of a voltage sensor domain. This conformational change of the protein is transmitted to the pore domain and eventually leads to pore opening. However, the voltage sensor domain may interact with two distinct gates in the pore domain: the activation gate (A-gate), involving the cytoplasmic S6 bundle crossing, and the pore gate (P-gate), located externally in the selectivity filter. How the voltage sensor moves and how tightly it interacts with these two gates on its way to adopt a relaxed conformation when the membrane is depolarized may critically determine the mode of Kv channel inactivation. In certain Kv channels, voltage sensor movement leads to a tight interaction with the P-gate, which may cause conformational changes that render the selectivity filter non-conductive (“P/C-type inactivation”). Other Kv channels may preferably undergo inactivation from pre-open closed-states during voltage sensor movement, because the voltage sensor temporarily uncouples from the A-gate. For this behavior, known as “preferential” closed-state inactivation, we introduce the term “A/C-type inactivation”. Mechanistically, P/C- and A/C-type inactivation represent two forms of “voltage sensor inactivation.”

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          Most cited references71

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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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            A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons.

            The role of back-propagating dendritic action potentials in the induction of long-term potentiation (LTP) was investigated in CA1 neurons by means of dendritic patch recordings and simultaneous calcium imaging. Pairing of subthreshold excitatory postsynaptic potentials (EPSPs) with back-propagating action potentials resulted in an amplification of dendritic action potentials and evoked calcium influx near the site of synaptic input. This pairing also induced a robust LTP, which was reduced when EPSPs were paired with non-back-propagating action potentials or when stimuli were unpaired. Action potentials thus provide a synaptically controlled, associative signal to the dendrites for Hebbian modifications of synaptic strength.
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              K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons.

              Pyramidal neurons receive tens of thousands of synaptic inputs on their dendrites. The dendrites dynamically alter the strengths of these synapses and coordinate them to produce an output in ways that are not well understood. Surprisingly, there turns out to be a very high density of transient A-type potassium ion channels in dendrites of hippocampal CA1 pyramidal neurons. These channels prevent initiation of an action potential in the dendrites, limit the back-propagation of action potentials into the dendrites, and reduce excitatory synaptic events. The channels act to prevent large, rapid dendritic depolarizations, thereby regulating orthograde and retrograde propagation of dendritic potentials.
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                Author and article information

                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Research Foundation
                1663-9812
                23 May 2012
                2012
                : 3
                : 100
                Affiliations
                [1] 1simpleInstitut für Zelluläre und Integrative Physiologie, Zentrum für Experimentelle Medizin, Universitätsklinikum Hamburg-Eppendorf Hamburg, Germany
                Author notes

                Edited by: Gildas Loussouarn, University of Nantes, France

                Reviewed by: Harley Takatsuna Kurata, University of British Columbia, Canada; Keith Elmslie, AT Still University of Health Sciences, USA

                *Correspondence: Robert Bähring, Institut für Zelluläre und Integrative Physiologie, Zentrum für Experimentelle Medizin, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. e-mail: r.baehring@ 123456uke.uni-hamburg.de

                This article was submitted to Frontiers in Pharmacology of Ion Channels and Channelopathies, a specialty of Frontiers in Pharmacology.

                Article
                10.3389/fphar.2012.00100
                3358694
                22654758
                27a8c129-e493-4337-9fd4-11032cce0eeb
                Copyright © 2012 Bähring, Barghaan, Westermeier and Wollberg.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                History
                : 16 March 2012
                : 04 May 2012
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 89, Pages: 8, Words: 7527
                Categories
                Pharmacology
                Review Article

                Pharmacology & Pharmaceutical medicine
                u-type inactivation,closed-state inactivation,p/c-type inactivation,kv channels

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