Dataset Information

A three-state multi-ion kinetic model for conduction properties of ClC-0 chloride channel.

ABSTRACT: A three-state, multiion kinetic model was proposed to enable the conduction properties of the mammalian channel ClC-0 to be well characterized. Using this rate-theory based model, the current-voltage and conductance-concentration relations were obtained. The five parameters needed were determined by fitting the data of conduction experiments of the wild-type ClC-0 and its K519C mutant. The model was then tested against available calculation and simulation data, and the energy differences between distinct chloride-occupancy states computed agreed with an independent calculation on the binding free energies solved by using the Poisson-Boltzmann equation. The average ion number of conduction and the ion passing duration calculated closely resembled the values obtained from Brownian dynamics simulations. According to the model, the decrease of conductance caused by mutating residue K519 to C519 can be attributed to the effect of K519C mutation on translocation rate constants. Our study sets up a theoretical model for ion permeation and conductance in ClC-0. It provides a starting point for experimentalists to test the three-state model, and would help in understanding the conduction mechanism of ClC-0.

SUBMITTER: Wang XQ

PROVIDER: S-EPMC2905080 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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A three-state multi-ion kinetic model for conduction properties of ClC-0 chloride channel.

Wang Xiao-Qing XQ Yu Tao T Sang Jian-Ping JP Zou Xian-Wu XW Chen Tsung-Yu TY Bolser Diana D Zou Xiaoqin X

Biophysical journal 20100701 2

A three-state, multiion kinetic model was proposed to enable the conduction properties of the mammalian channel ClC-0 to be well characterized. Using this rate-theory based model, the current-voltage and conductance-concentration relations were obtained. The five parameters needed were determined by fitting the data of conduction experiments of the wild-type ClC-0 and its K519C mutant. The model was then tested against available calculation and simulation data, and the energy differences between ...[more]

PMID: 20643064

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Project description:CLC-0, a prototype Cl- channel in the CLC family, employs two gating mechanisms that control its ion-permeation pore: fast gating and slow gating. The negatively-charged sidechain of a pore glutamate residue, E166, is known to be the fast gate, and the swinging of this sidechain opens or closes the pore of CLC-0 on the millisecond time scale. The other gating mechanism, slow gating, operates with much slower kinetics in the range of seconds to tens or even hundreds of seconds, and it is thought to involve still-unknown conformational rearrangements. Here, we find that low intracellular pH (pHi) facilitates the closure of the CLC-0's slow gate, thus generating current inhibition. The rate of low pHi-induced current inhibition increases with intracellular H+ concentration ([H+]i)-the time constants of current inhibition by low pHi = 4.5, 5.5 and 6 are roughly 0.1, 1 and 10 sec, respectively, at room temperature. In comparison, the time constant of the slow gate closure at pHi = 7.4 at room temperature is hundreds of seconds. The inhibition by low pHi is significantly less prominent in mutants favoring the slow-gate open state (such as C212S and Y512A), further supporting the fact that intracellular H+ enhances the slow-gate closure in CLC-0. A fast inhibition by low pHi causes an apparent inverted voltage-dependent activation in the wild-type CLC-0, a behavior similar to those in some channel mutants such as V490W in which only membrane hyperpolarization can open the channel. Interestingly, when V490W mutation is constructed in the background of C212S or Y512A mutation, the inverted voltage-dependent activation disappears. We propose that the slow kinetics of CLC-0's slow-gate closure may be due to low [H+]i rather than due to the proposed large conformational change of the channel protein. Our results also suggest that the inverted voltage-dependent opening observed in some mutant channels may result from fast closure of the slow gate by the mutations.

Project description:The opening and closing of chloride (Cl-) channels in the ClC family are thought to tightly couple to ion permeation through the channel pore. In the prototype channel of the family, the ClC-0 channel from the Torpedo electric organ, the opening-closing of the pore in the millisecond time range known as "fast gating" is regulated by both external and internal Cl- ions. Although the external Cl- effect on the fast-gate opening has been extensively studied at a quantitative level, the internal Cl- regulation remains to be characterized. In this study, we examine the internal Cl- effects and the electrostatic controls of the fast-gating mechanism. While having little effect on the opening rate, raising [Cl-]i reduces the closing rate (or increases the open time) of the fast gate, with an apparent affinity of >1 M, a value very different from the one observed in the external Cl- regulation on the opening rate. Mutating charged residues in the pore also changes the fast-gating properties-the effects are more prominent on the closing rate than on the opening rate, a phenomenon similar to the effect of [Cl-]i on the fast gating. Thus, the alteration of fast-gate closing by charge mutations may come from a combination of two effects: a direct electrostatic interaction between the manipulated charge and the negatively charged glutamate gate and a repulsive force on the gate mediated by the permeant ion. Likewise, the regulations of internal Cl- on the fast gating may also be due to the competition of Cl- with the glutamate gate as well as the overall more negative potential brought to the pore by the binding of Cl-. In contrast, the opening rate of the fast gate is only minimally affected by manipulations of [Cl-]i and charges in the inner pore region. The very different nature of external and internal Cl- regulations on the fast gating thus may suggest that the opening and the closing of the fast gate are not microscopically reversible processes, but form a nonequilibrium cycle in the ClC-0 fast-gating mechanism.

Dataset Information

A three-state multi-ion kinetic model for conduction properties of ClC-0 chloride channel.

Publications

A three-state multi-ion kinetic model for conduction properties of ClC-0 chloride channel.

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