Investigation of an inward-rectification in small-conductance calcium-activated potassium channels due to binding of divalent cations

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Investigation of an inward-rectification in small-conductance calcium-activated potassium channels due to binding of divalent cations

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Title: Investigation of an inward-rectification in small-conductance calcium-activated potassium channels due to binding of divalent cations
Author: Cho, Min-Jeong
Abstract: Small conductance calcium-activated potassium channels (SK channels) are voltage-independent, potassium-selective, and calcium-activated ion channels that act as important modulators of neuronal excitability through the slow afterhyperpolarization(sAHP). The sAHP occurs when action potential increases the concentration of intracellular calcium, which activates SK channels and let potassium to pass through the channels. Once SK channels open, the movement of potassium from inside to outside of the cell causes hyperpolarization of the cell, in which membrane potential becomes more negative than the resting potential. By holding the membrane voltage below the resting potential, SK channels prevent cells from engaging in continuous and repeated firing of action potentials, which can have deleterious effects on cells that are not ready to fire again. Through causing the sAHP, SK channels act as important players of neuronal excitability and serve as novel targets for studying various pathologies related to the sAHP. Among various properties of SK channels, an underlying mechanism of an inwardly-rectifying behavior, in which the outward currents are blocked more than the inward currents, has not been fully understood yet. Serine-359 in each subunits of a SK channel tetramer is known to contribute to an inward rectification by interacting with intracellular divalent cations through an electrostatic interaction. These residues comprise K+- selectivity filter of SK channels, and blockage of this site by divalent ions contributes to an inward rectification. However, the contribution of each serine residues from each subunit to the interaction with divalent cations has not been studied. Therefore, the biophysical properties of binding interaction between barium and different combination of serine residues were investigated using electrophysiology techniques and mutational studies. A clone of wild-type and mutant (four serine-359 mutated to alanine) SK channel were expressed in Xenopus oocytes, and the current-voltage relationship of SK channels was studied using patch-clamping method. It was found that IC50 of wild-type at 60mV was 4.1e-6 while that of mutant was 2.7e-4. There are sixty-five fold differences between the IC50 values for wild-type and mutant, which indicates that serine-359 residues contribute to an inward-rectification. Also, it was found that the inward-rectification is dependent on voltage, which is also consistent with the finding from Soh and Park., 2002. Although the original aim of study was to investigate the energetic binding of barium to each subunit of SK channels, the study of different combination of mutations on subunits will be done as a future study.
Department: Biological Sciences, School of
Subject: College of Natural Sciences potassium channels neuronal excitability slow afterhyperpolarization sAHP small conductance calcium-activated potassium channels SK channels inward rectification barium
URI: http://hdl.handle.net/2152/13410
Date: 2010

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