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Allosteric gating of a large conductance Ca-activated K+ channel.

Cox DH, Cui J, Aldrich RW - J. Gen. Physiol. (1997)

Bottom Line: Physiol.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.

ABSTRACT
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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mslo (A) and voltage-dependent MWC model (B) Ca2+  dose-response curves are plotted  for seven different voltages ranging from −40 to +80 mV in 20-mV  steps (symbols). Each curve in A  and B has been fitted with the Hill  equation (Eq. 8) (solid curves) and  the parameters of these fits are  plotted as a function of voltage in  C, D (see footnote 4), and E. mslo  data and fit parameters are indicated with (•). Simulated data  and fit parameters are indicated  with (○). Data are from patch 1  (Fig. 5 A). The voltage-dependent  MWC model parameters used for  these simulations are those listed  in Table III. Similar data from  patch 1 were displayed in Cui et al.  (1997) (Fig. 13).
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Figure 8: mslo (A) and voltage-dependent MWC model (B) Ca2+ dose-response curves are plotted for seven different voltages ranging from −40 to +80 mV in 20-mV steps (symbols). Each curve in A and B has been fitted with the Hill equation (Eq. 8) (solid curves) and the parameters of these fits are plotted as a function of voltage in C, D (see footnote 4), and E. mslo data and fit parameters are indicated with (•). Simulated data and fit parameters are indicated with (○). Data are from patch 1 (Fig. 5 A). The voltage-dependent MWC model parameters used for these simulations are those listed in Table III. Similar data from patch 1 were displayed in Cui et al. (1997) (Fig. 13).

Mentions: The steady state behavior of mslo and model channels can also be compared by looking at Popen as a function of [Ca]. In Fig. 8, the data of Fig. 5 A are shown converted to Ca2+ dose-response form (filled circles). Simulated voltage-dependent MWC model data are included as well (open circles). Each curve represents a different voltage. Both real data and simulated model points were fitted (solid curves) with the Hill equation (Hill, 1910): 8\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}G/G_{max}= \left[ A\frac{1}{1+ \left( \frac{K_{D}}{[Ca]} \right) ^{n}} \right] \end{equation*}\end{document}


Allosteric gating of a large conductance Ca-activated K+ channel.

Cox DH, Cui J, Aldrich RW - J. Gen. Physiol. (1997)

mslo (A) and voltage-dependent MWC model (B) Ca2+  dose-response curves are plotted  for seven different voltages ranging from −40 to +80 mV in 20-mV  steps (symbols). Each curve in A  and B has been fitted with the Hill  equation (Eq. 8) (solid curves) and  the parameters of these fits are  plotted as a function of voltage in  C, D (see footnote 4), and E. mslo  data and fit parameters are indicated with (•). Simulated data  and fit parameters are indicated  with (○). Data are from patch 1  (Fig. 5 A). The voltage-dependent  MWC model parameters used for  these simulations are those listed  in Table III. Similar data from  patch 1 were displayed in Cui et al.  (1997) (Fig. 13).
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Figure 8: mslo (A) and voltage-dependent MWC model (B) Ca2+ dose-response curves are plotted for seven different voltages ranging from −40 to +80 mV in 20-mV steps (symbols). Each curve in A and B has been fitted with the Hill equation (Eq. 8) (solid curves) and the parameters of these fits are plotted as a function of voltage in C, D (see footnote 4), and E. mslo data and fit parameters are indicated with (•). Simulated data and fit parameters are indicated with (○). Data are from patch 1 (Fig. 5 A). The voltage-dependent MWC model parameters used for these simulations are those listed in Table III. Similar data from patch 1 were displayed in Cui et al. (1997) (Fig. 13).
Mentions: The steady state behavior of mslo and model channels can also be compared by looking at Popen as a function of [Ca]. In Fig. 8, the data of Fig. 5 A are shown converted to Ca2+ dose-response form (filled circles). Simulated voltage-dependent MWC model data are included as well (open circles). Each curve represents a different voltage. Both real data and simulated model points were fitted (solid curves) with the Hill equation (Hill, 1910): 8\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}G/G_{max}= \left[ A\frac{1}{1+ \left( \frac{K_{D}}{[Ca]} \right) ^{n}} \right] \end{equation*}\end{document}

Bottom Line: Physiol.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus