ArticleThe Journal of biological chemistry2012
Intracellular β-nicotinamide adenine dinucleotide inhibits the skeletal muscle ClC-1 chloride channel.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Biophysical and Pharmacological Insights to CLC Chloride Channels.Handbook of experimental pharmacology · 2024Article
- ClC-1 Chloride Channel: Inputs on the Structure-Function Relationship of Myotonia Congenita-Causing Mutations.Biomedicines · 2023Review
- Skeletal muscle ClC-1 chloride channels in health and diseases.Pflugers Archiv : European journal of physiology · 2020Review
- Article
- Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita.Frontiers in neurology · 2020Review
- Structure of the human ClC-1 chloride channel.PLoS biology · 2019Article
- ClC Channels and Transporters: Structure, Physiological Functions, and Implications in Human Chloride Channelopathies.Frontiers in pharmacology · 2017Review
- Regulatory Conformational Coupling between CLC Anion Channel Membrane and Cytoplasmic Domains.Biophysical journal · 2016Article
- Role of CBS and Bateman Domains in Phosphorylation-Dependent Regulation of a CLC Anion Channel.Biophysical journal · 2016Article
- Role of physiological ClC-1 Cl- ion channel regulation for the excitability and function of working skeletal muscle.The Journal of general physiology · 2016Review
- Structure and gating of CLC channels and exchangers.The Journal of physiology · 2015Review
- ClC-1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype-phenotype correlation.The Journal of physiology · 2015Article
- Discovery of CLC transport proteins: cloning, structure, function and pathophysiology.The Journal of physiology · 2015Review
- ClC-1 chloride channels: state-of-the-art research and future challenges.Frontiers in cellular neuroscience · 2015Review
- Common gating of both CLC transporter subunits underlies voltage-dependent activation of the 2Cl-/1H+ exchanger ClC-7/Ostm1.The Journal of biological chemistry · 2013Article
- Regulatory phosphorylation induces extracellular conformational changes in a CLC anion channel.Biophysical journal · 2013Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.