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      Coupling between Voltage Sensor Activation, Ca 2+ Binding and Channel Opening in Large Conductance (BK) Potassium Channels

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          Abstract

          To determine how intracellular Ca 2+ and membrane voltage regulate the gating of large conductance Ca 2+-activated K + (BK) channels, we examined the steady-state and kinetic properties of mSlo1 ionic and gating currents in the presence and absence of Ca 2+ over a wide range of voltage. The activation of unliganded mSlo1 channels can be accounted for by allosteric coupling between voltage sensor activation and the closed (C) to open (O) conformational change (Horrigan, F.T., and R.W. Aldrich. 1999. J. Gen. Physiol. 114:305–336; Horrigan, F.T., J. Cui, and R.W. Aldrich. 1999. J. Gen. Physiol. 114:277–304). In 0 Ca 2+, the steady-state gating charge-voltage (Q SS-V) relationship is shallower and shifted to more negative voltages than the conductance-voltage (G K-V) relationship. Calcium alters the relationship between Q-V and G-V, shifting both to more negative voltages such that they almost superimpose in 70 μM Ca 2+. This change reflects a differential effect of Ca 2+ on voltage sensor activation and channel opening. Ca 2+ has only a small effect on the fast component of ON gating current, indicating that Ca 2+ binding has little effect on voltage sensor activation when channels are closed. In contrast, open probability measured at very negative voltages (less than −80 mV) increases more than 1,000-fold in 70 μM Ca 2+, demonstrating that Ca 2+ increases the C-O equilibrium constant under conditions where voltage sensors are not activated. Thus, Ca 2+ binding and voltage sensor activation act almost independently, to enhance channel opening. This dual-allosteric mechanism can reproduce the steady-state behavior of mSlo1 over a wide range of conditions, with the assumption that activation of individual Ca 2+ sensors or voltage sensors additively affect the energy of the C-O transition and that a weak interaction between Ca 2+ sensors and voltage sensors occurs independent of channel opening. By contrast, macroscopic I K kinetics indicate that Ca 2+ and voltage dependencies of C-O transition rates are complex, leading us to propose that the C-O conformational change may be described by a complex energy landscape.

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          Most cited references61

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          Shaker potassium channel gating. III: Evaluation of kinetic models for activation

          Predictions of different classes of gating models involving identical conformational changes in each of four subunits were compared to the gating behavior of Shaker potassium channels without N-type inactivation. Each model was tested to see if it could simulate the voltage dependence of the steady state open probability, and the kinetics of the single-channel currents, macroscopic ionic currents and macroscopic gating currents using a single set of parameters. Activation schemes based upon four identical single-step activation processes were found to be incompatible with the experimental results, as were those involving a concerted, opening transition. A model where the opening of the channel requires two conformational changes in each of the four subunits can adequately account for the steady state and kinetic behavior of the channel. In this model, the gating in each subunit is independent except for a stabilization of the open state when all four subunits are activated, and an unstable closed conformation that the channel enters after opening. A small amount of negative cooperativity between the subunits must be added to account quantitatively for the dependence of the activation time course on holding voltage.
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            mSlo, a complex mouse gene encoding "maxi" calcium-activated potassium channels.

            Complementary DNAs (cDNAs) from mSlo, a gene encoding calcium-activated potassium channels, were isolated from mouse brain and skeletal muscle, sequenced, and expressed in Xenopus oocytes. The mSlo-encoded channel resembled "maxi" or BK (high conductance) channel types; single channel conductance was 272 picosiemens with symmetrical potassium concentrations. Whole cell and single channel currents were blocked by charybdotoxin, iberiotoxin, and tetraethylammonium ion. A large number of variant mSlo cDNAs were isolated, indicating that several diverse mammalian BK channel types are produced by a single gene.
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              Allosteric Gating of a Large Conductance Ca-activated K+ Channel

              Large-conductance Ca-activated potassium channels (BK channels) are uniquely sensitive to both membrane potential and intracellular Ca2+. Recent work has demonstrated that in the gating of these channels there are voltage-sensitive steps that are separate from Ca2+ binding steps. Based on this result and the macroscopic steady state and kinetic properties of the cloned BK channel mslo, we have recently proposed a general kinetic scheme to describe the interaction between voltage and Ca2+ in the gating of the mslo channel (Cui, J., D.H. Cox, and R.W. Aldrich. 1997. J. Gen. Physiol. In press.). This scheme supposes that the channel exists in two main conformations, closed and open. The conformational change between closed and open is voltage dependent. Ca2+ binds to both the closed and open conformations, but on average binds more tightly to the open conformation and thereby promotes channel opening. Here we describe the basic properties of models of this form and test their ability to mimic mslo macroscopic steady state and kinetic behavior. The simplest form of this scheme corresponds to a voltage-dependent version of the Monod-Wyman-Changeux (MWC) model of allosteric proteins. The success of voltage-dependent MWC models in describing many aspects of mslo gating suggests that these channels may share a common molecular mechanism with other allosteric proteins whose behaviors have been modeled using the MWC formalism. We also demonstrate how this scheme can arise as a simplification of a more complex scheme that is based on the premise that the channel is a homotetramer with a single Ca2+ binding site and a single voltage sensor in each subunit. Aspects of the mslo data not well fitted by the simplified scheme will likely be better accounted for by this more general scheme. The kinetic schemes discussed in this paper may be useful in interpreting the effects of BK channel modifications or mutations.
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                Author and article information

                Journal
                J Gen Physiol
                The Journal of General Physiology
                The Rockefeller University Press
                0022-1295
                1540-7748
                September 2002
                : 120
                : 3
                : 267-305
                Affiliations
                [1 ]Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
                [2 ]Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute Stanford University School of Medicine, Stanford, CA 94305
                Author notes

                Address correspondence to Dr. Frank T. Horrigan, Department of Physiology, University of Pennsylvania School of Medicine, A401 Richards, 3700 Hamilton Walk, Philadelphia, PA 19104. Fax: (215) 573-5851; E-mail: horrigan@ 123456mail.med.upenn.edu

                Article
                20028605
                10.1085/jgp.20028605
                2229516
                12198087
                57dbf69f-225f-4bac-b7e4-ffb61b664742
                Copyright © 2002, The Rockefeller University Press
                History
                : 10 April 2002
                : 26 June 2002
                : 27 June 2002
                Categories
                Article

                Anatomy & Physiology
                gating current,bk channel,ion channel gating,calcium,potassium channel
                Anatomy & Physiology
                gating current, bk channel, ion channel gating, calcium, potassium channel

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