Intracellular β-Nicotinamide Adenine Dinucleotide Inhibits the Skeletal Muscle ClC-1 Chloride Channel

Bennetts, Brett; Yu, Yawei; Chen, Tsung‐Yu; Parker, Michael W.

doi:10.1074/jbc.m111.327551

Cited by 23 publications

(29 citation statements)

References 58 publications

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“…In the instance that the mutations affected NAD þ sensitivity independently, we would expect that double-mutant channels would be less sensitive to NAD þ than either of the parental singlemutants. Supporting this hypothesis, mutation G200R on helix D also reduces sensitivity to intracellular NAD 50 , and G200R/ D579K mutant channels were less sensitive to 3 mM NAD that either of the parental mutants ( Supplementary Fig. S6).…”

Section: Resultsmentioning

confidence: 67%

“…Intracellular metabolites such as ATP and NAD þ affect ClC-1 function by shifting the voltage dependence of common gating to more positive potentials and simultaneously reducing the minimum value of common gating curves [45][46][47][48][49][50] . These molecules bind to tandem CBS domains, which form the predominant structural feature of the extensive ClC-1 intracellular carboxy terminus.…”

Section: Resultsmentioning

confidence: 99%

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Molecular determinants of common gating of a ClC chloride channel

Bennetts

Parker

2013

Nat Commun

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Uniquely, the ClC family harbours dissipative channels and anion/H þ transporters that share unprecedented functional characteristics. ClC-1 channels are homodimers in which each monomer supports an identical pore carrying three anion-binding sites. Transient occupancy of the extracellular binding site by a conserved glutamate residue, E232, independently gates each pore. A common gate, the molecular basis of which is unknown, closes both pores simultaneously. Mutations affecting common gating underlie myotonia congenita in humans. Here we show that the common gate likely occludes the channel pore via interaction of E232 with a highly conserved tyrosine, Y578, at the central anion-binding site. We also identify structural linkages important for coordination of common gating between subunits and modulation by intracellular molecules. Our data reveal important molecular determinants of common gating of ClC channels and suggest that the molecular mechanism is an evolutionary vestige of coupled anion/H þ transport.

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Section: Resultsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Molecular determinants of common gating of a ClC chloride channel

Bennetts

Parker

2013

Nat Commun

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“…and β-nicotinamide adenine dinucleotide (Bennetts et al 2012) through binding to the CBS domains in its cytoplasmic tail. This may provide a physiologically important coupling to muscle metabolism.…”

Section: Clc-1: a CLmentioning

confidence: 99%

Discovery of CLC transport proteins: cloning, structure, function and pathophysiology

Jentsch

2015

J Physiol

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After providing a personal description of the convoluted path leading 25 years ago to the molecular identification of the Torpedo Cl − channel ClC-0 and the discovery of the CLC gene family, I succinctly describe the general structural and functional features of these ion transporters before giving a short overview of mammalian CLCs. These can be categorized into plasma membrane Cl − channels and vesicular Cl − /H + -exchangers. They are involved in the regulation of membrane excitability, transepithelial transport, extracellular ion homeostasis, endocytosis and lysosomal function. Diseases caused by CLC dysfunction include myotonia, neurodegeneration, deafness, blindness, leukodystrophy, male infertility, renal salt loss, kidney stones and osteopetrosis, revealing a surprisingly broad spectrum of biological roles for chloride transport that was unsuspected when I set out to clone the first voltage-gated chloride channel.

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“…Although the biophysical mechanisms of CLC Cl À and H þ transport have been studied extensively, relatively little is known about the molecular mechanisms of CLC regulation. Numerous CLCs are regulated by phosphorylation (3)(4)(5)(6), intracellular adenosine ligands (7,8), accessory proteins (9,10), and extracellular Ca 2þ (11).…”

Section: Introductionmentioning

confidence: 99%

Role of CBS and Bateman Domains in Phosphorylation-Dependent Regulation of a CLC Anion Channel

Yamada

Krzeminski

Bozóky

et al. 2016

Biophysical Journal

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Eukaryotic CLC anion channels and transporters are homodimeric proteins composed of multiple a-helical membrane domains and large cytoplasmic C-termini containing two cystathionine-b-synthase domains (CBS1 and CBS2) that dimerize to form a Bateman domain. The Bateman domains of adjacent CLC subunits interact to form a Bateman domain dimer. The functions of CLC CBS and Bateman domains are poorly understood. We utilized the Caenorhabditis elegans CLC-1/2/Ka/ Kb anion channel homolog CLH-3b to characterize the regulatory roles of CLC cytoplasmic domains. CLH-3b activity is reduced by phosphorylation or deletion of a 14-amino-acid activation domain (AD) located on the linker connecting CBS1 and CBS2. We demonstrate here that phosphorylation-dependent reductions in channel activity require an intact Bateman domain dimer and concomitant phosphorylation or deletion of both ADs. Regulation of a CLH-3b AD deletion mutant is reconstituted by intracellular perfusion with recombinant 14-amino-acid AD peptides. The sulfhydryl reactive reagent 2-(trimethylammonium)ethyl methanethiosulfonate bromide (MTSET) alters in a phosphorylation-dependent manner the activity of channels containing single cysteine residues that are engineered into the short intracellular loop connecting membrane a-helices H and I (H-I loop), the AD, CBS1, and CBS2. In contrast, MTSET has no effect on channels in which cysteine residues are engineered into intracellular regions that are dispensable for regulation. These studies together with our previous work suggest that binding and unbinding of the AD to the Bateman domain dimer induces conformational changes that are transduced to channel membrane domains via the H-I loop. Our findings provide new, to our knowledge, insights into the roles of CLC Bateman domains and the structurefunction relationships that govern the regulation of CLC protein activity by diverse ligands and signaling pathways.

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Intracellular β-Nicotinamide Adenine Dinucleotide Inhibits the Skeletal Muscle ClC-1 Chloride Channel

Cited by 23 publications

References 58 publications

Molecular determinants of common gating of a ClC chloride channel

Molecular determinants of common gating of a ClC chloride channel

Discovery of CLC transport proteins: cloning, structure, function and pathophysiology

Role of CBS and Bateman Domains in Phosphorylation-Dependent Regulation of a CLC Anion Channel

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