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Intracellular β-nicotinamide adenine dinucleotide inhibits the skeletal muscleClC-1 chloride channel.
Bennetts B
,
Yu Y
,
Chen TY
,
Parker MW
.
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ClC-1 is the dominant sarcolemmal chloride channel and plays an important role in regulating membrane excitability that is underscored by ClC-1 mutations in congenital myotonia. Here we show that the coenzyme β-nicotinamide adenine dinucleotide (NAD), an important metabolic regulator, robustly inhibits ClC-1 when included in the pipette solution in whole cell patch clamp experiments and when transiently applied to inside-out patches. The oxidized (NAD(+)) form of the coenzyme was more efficacious than the reduced (NADH) form, and inhibition by both was greatly enhanced by acidification. Molecular modeling, based on the structural coordinates of the homologous ClC-5 and CmClC proteins and in silico docking, suggest that NAD(+) binds with the adenine base deep in a cleft formed by ClC-1 intracellular cystathionine β-synthase domains, and the nicotinamide base interacts with the membrane-embedded channel domain. Consistent with predictions from the models, mutation of residues in cystathionine β-synthase and channel domains either attenuated (G200R, T636A, H847A) or abrogated (L848A) the effect of NAD(+). In addition, the myotonic mutations G200R and Y261C abolished potentiation of NAD(+) inhibition at low pH. Our results identify a new biological role for NAD and suggest that the main physiological relevance may be the exquisite sensitivity to intracellular pH that NAD(+) inhibition imparts to ClC-1 gating. These findings are consistent with the reduction of sarcolemmal chloride conductance that occurs upon acidification of skeletal muscle and suggest a previously unexplored mechanism in the pathophysiology of myotonia.
Accardi,
Fast and slow gating relaxations in the muscle chloride channel CLC-1.
2000, Pubmed,
Xenbase
Accardi,
Fast and slow gating relaxations in the muscle chloride channel CLC-1.
2000,
Pubmed
,
Xenbase
Accardi,
Drastic reduction of the slow gate of human muscle chloride channel (ClC-1) by mutation C277S.
2001,
Pubmed
,
Xenbase
Bennetts,
Inhibition of skeletal muscle ClC-1 chloride channels by low intracellular pH and ATP.
2007,
Pubmed
Bennetts,
Cytoplasmic ATP-sensing domains regulate gating of skeletal muscle ClC-1 chloride channels.
2005,
Pubmed
Bretag,
Muscle chloride channels.
1987,
Pubmed
Bykova,
Large movement in the C terminus of CLC-0 chloride channel during slow gating.
2006,
Pubmed
Carugo,
NADP-dependent enzymes. I: Conserved stereochemistry of cofactor binding.
1997,
Pubmed
Chen,
Chloride conductance in mouse muscle is subject to post-transcriptional compensation of the functional Cl- channel 1 gene dosage.
1997,
Pubmed
Chen,
Extracellular zinc ion inhibits ClC-0 chloride channels by facilitating slow gating.
1998,
Pubmed
,
Xenbase
De Angeli,
ATP binding to the C terminus of the Arabidopsis thaliana nitrate/proton antiporter, AtCLCa, regulates nitrate transport into plant vacuoles.
2009,
Pubmed
Dutzler,
Structural basis for ion conduction and gating in ClC chloride channels.
2004,
Pubmed
Dutzler,
X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity.
2002,
Pubmed
Eisenberg,
VERIFY3D: assessment of protein models with three-dimensional profiles.
1997,
Pubmed
Feng,
Structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle.
2010,
Pubmed
Fitts,
Cellular mechanisms of muscle fatigue.
1994,
Pubmed
Grahnert,
Involvement of P2X receptors in the NAD(+)-induced rise in [Ca (2+)] (i) in human monocytes.
2009,
Pubmed
Guex,
SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling.
1997,
Pubmed
Hermansen,
Blood and muscle pH after maximal exercise in man.
1972,
Pubmed
Houtkooper,
The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways.
2010,
Pubmed
Jain,
Surflex-Dock 2.1: robust performance from ligand energetic modeling, ring flexibility, and knowledge-based search.
2007,
Pubmed
Klein,
Extracellular NAD(+) induces a rise in [Ca(2+)](i) in activated human monocytes via engagement of P2Y(1) and P2Y(11) receptors.
2009,
Pubmed
Lee,
Mechanisms of calcium signaling by cyclic ADP-ribose and NAADP.
1997,
Pubmed
Li,
Oxidation and reduction control of the inactivation gating of Torpedo ClC-0 chloride channels.
2005,
Pubmed
,
Xenbase
Lucas,
Binding of S-methyl-5'-thioadenosine and S-adenosyl-L-methionine to protein MJ0100 triggers an open-to-closed conformational change in its CBS motif pair.
2010,
Pubmed
Ma,
Movement of hClC-1 C-termini during common gating and limits on their cytoplasmic location.
2011,
Pubmed
Mailänder,
Novel muscle chloride channel mutations and their effects on heterozygous carriers.
1996,
Pubmed
Markovic,
The structure of the cytoplasmic domain of the chloride channel ClC-Ka reveals a conserved interaction interface.
2007,
Pubmed
Menteyne,
Generation of specific Ca(2+) signals from Ca(2+) stores and endocytosis by differential coupling to messengers.
2006,
Pubmed
Metzger,
Variations in cross-bridge attachment rate and tension with phosphorylation of myosin in mammalian skinned skeletal muscle fibers. Implications for twitch potentiation in intact muscle.
1989,
Pubmed
Metzger,
Role of intracellular pH in muscle fatigue.
1987,
Pubmed
Meyer,
Nucleotide recognition by the cytoplasmic domain of the human chloride transporter ClC-5.
2007,
Pubmed
,
Xenbase
Meyer,
Crystal structure of the cytoplasmic domain of the chloride channel ClC-0.
2006,
Pubmed
Moore,
The ionization constant of nicotinamide-adenine dinucleotide.
1969,
Pubmed
Niemeyer,
Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies.
2004,
Pubmed
Notredame,
T-Coffee: A novel method for fast and accurate multiple sequence alignment.
2000,
Pubmed
Pedersen,
Increased excitability of acidified skeletal muscle: role of chloride conductance.
2005,
Pubmed
Pedersen,
Intracellular acidosis enhances the excitability of working muscle.
2004,
Pubmed
Pusch,
Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CIC-1 chloride channel.
1995,
Pubmed
Revollo,
The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells.
2004,
Pubmed
Roos,
Intracellular pH transients in rat diaphragm muscle measured with DMO.
1978,
Pubmed
Rychkov,
Interaction of hydrophobic anions with the rat skeletal muscle chloride channel ClC-1: effects on permeation and gating.
2001,
Pubmed
Rychkov,
Concentration and pH dependence of skeletal muscle chloride channel ClC-1.
1996,
Pubmed
,
Xenbase
Sahlin,
Intracellular pH and bicarbonate concentration in human muscle during recovery from exercise.
1978,
Pubmed
Sahlin,
Lactate content and pH in muscle obtained after dynamic exercise.
1976,
Pubmed
Sano,
Immunocyte Ca2+ influx system mediated by LTRPC2.
2001,
Pubmed
Scott,
CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations.
2004,
Pubmed
Sejersted,
Dynamics and consequences of potassium shifts in skeletal muscle and heart during exercise.
2000,
Pubmed
Steinmeyer,
Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel.
1991,
Pubmed
,
Xenbase
Thompson,
Muscle fatigue in frog semitendinosus: role of intracellular pH.
1992,
Pubmed
Tseng,
Binding of ATP to the CBS domains in the C-terminal region of CLC-1.
2011,
Pubmed
,
Xenbase
Tseng,
Cytoplasmic ATP inhibition of CLC-1 is enhanced by low pH.
2007,
Pubmed
,
Xenbase
Wellhauser,
ATP induces conformational changes in the carboxyl-terminal region of ClC-5.
2011,
Pubmed
,
Xenbase
Wellhauser,
Nucleotides bind to the C-terminus of ClC-5.
2006,
Pubmed
Wilson,
Relationship of muscular fatigue to pH and diprotonated Pi in humans: a 31P-NMR study.
1988,
Pubmed
Wollnik,
Identification of functionally important regions of the muscular chloride channel CIC-1 by analysis of recessive and dominant myotonic mutations.
1997,
Pubmed
,
Xenbase
Yamada,
The simultaneous measurement of nicotinamide adenine dinucleotide and related compounds by liquid chromatography/electrospray ionization tandem mass spectrometry.
2006,
Pubmed
Yang,
Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival.
2007,
Pubmed
Zhang,
ATP inhibition of CLC-1 is controlled by oxidation and reduction.
2008,
Pubmed
,
Xenbase
Zifarelli,
Intracellular regulation of human ClC-5 by adenine nucleotides.
2009,
Pubmed
