Stoelting, Gabriel, Teodorescu, Georgeta, Begemann, Birgit, Schubert, Julian, Nabbout, Rima, Toliat, Mohammad Reza, Sander, Thomas, Nuernberg, Peter, Lerche, Holger and Fahlke, Christoph ORCID: 0000-0001-8602-9952 (2013). Regulation of ClC-2 gating by intracellular ATP. Pflugers Arch., 465 (10). S. 1423 - 1438. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-2013

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Abstract

ClC-2 is a voltage-dependent chloride channel that activates slowly at voltages negative to the chloride reversal potential. Adenosine triphosphate (ATP) and other nucleotides have been shown to bind to carboxy-terminal cystathionine--synthase (CBS) domains of ClC-2, but the functional consequences of binding are not sufficiently understood. We here studied the effect of nucleotides on channel gating using single-channel and whole-cell patch clamp recordings on transfected mammalian cells. ATP slowed down macroscopic activation and deactivation time courses in a dose-dependent manner. Removal of the complete carboxy-terminus abolishes the effect of ATP, suggesting that CBS domains are necessary for ATP regulation of ClC-2 gating. Single-channel recordings identified long-lasting closed states of ATP-bound channels as basis of this gating deceleration. ClC-2 channel dimers exhibit two largely independent protopores that are opened and closed individually as well as by a common gating process. A seven-state model of common gating with altered voltage dependencies of opening and closing transitions for ATP-bound states correctly describes the effects of ATP on macroscopic and microscopic ClC-2 currents. To test for a potential pathophysiological impact of ClC-2 regulation by ATP, we studied ClC-2 channels carrying naturally occurring sequence variants found in patients with idiopathic generalized epilepsy, G715E, R577Q, and R653T. All naturally occurring sequence variants accelerate common gating in the presence but not in the absence of ATP. We propose that ClC-2 uses ATP as a co-factor to slow down common gating for sufficient electrical stability of neurons under physiological conditions.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Stoelting, GabrielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teodorescu, GeorgetaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Begemann, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schubert, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nabbout, RimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toliat, Mohammad RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fahlke, ChristophUNSPECIFIEDorcid.org/0000-0001-8602-9952UNSPECIFIED
URN: urn:nbn:de:hbz:38-475228
DOI: 10.1007/s00424-013-1286-0
Journal or Publication Title: Pflugers Arch.
Volume: 465
Number: 10
Page Range: S. 1423 - 1438
Date: 2013
Publisher: SPRINGER HEIDELBERG
Place of Publication: HEIDELBERG
ISSN: 1432-2013
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
IDIOPATHIC GENERALIZED EPILEPSY; MUSCLE CHLORIDE CHANNELS; CYTOPLASMIC DOMAIN; CBS DOMAINS; MUTATIONS; REVEALS; CIC-2; INHIBITION; MECHANISM; TERMINUSMultiple languages
PhysiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47522

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