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57  structures 3515  species 1  interaction 7727  sequences 38  architectures

Family: Voltage_CLC (PF00654)

Summary: Voltage gated chloride channel

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This is the Wikipedia entry entitled "Chloride channel". More...

Chloride channel Edit Wikipedia article

1ots opm.gif
Clc chloride channel
Symbol Voltage_CLC
Pfam PF00654
InterPro IPR014743
SCOP 1kpl
TCDB 1.A.11
OPM superfamily 10
OPM protein 1ots
CDD cd00400

Chloride channels are a superfamily of poorly understood ion channels consisting of approximately 13 members.

Chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell proliferation and differentiation. Based on sequence homology the chloride channels can be subdivided into a number of groups. The importance of one such group, the CLC family of chloride channels, can be seen from the diseases that develop when the channel does not function normally.

This family of ion channels contains 10 or 12 transmembrane helices. Each protein forms a single pore. It has been shown that some members of this family form homodimers. In terms of primary structure, they are unrelated to known cation channels or other types of anion channels. Three CLC subfamilies are found in animals. CLC-1 (P35523) is involved in setting and restoring the resting membrane potential of skeletal muscle, while other channels play important parts in solute concentration mechanisms in the kidney [3]. These proteins contain two CBS domains. Chloride channels are also important for maintaining safe ion concentrations within plant cells.[1]


Bartter's syndrome, which is associated with renal salt wasting and hypokalemic alkalosis, is due to the defective transport of chloride ions and associated ions in the thick ascending loop of Henle. CLCNKB has been implicated.

Another inherited disease that affects the kidney organs is Dent's Disease, characterised by low molecular weight proteinuria and hypercalciuria where mutations in CLCN5 are implicated.

Thomsen disease is associated with dominant mutations and Becker disease with recessive mutations in CLCN1.

Cystic fibrosis is caused by a mutation in the DF508 region of the CFTR gene, which prevents the proper folding of the protein and subsequent degradation, resulting in decreased numbers of chloride channels in the body. This causes the build up of mucus in the body and chronic infections.


Chloride channels are important for setting cell resting membrane potential and maintaining proper cell volume. These channels conduct Cl as well as other anions such as HCO3, I, SCN, and NO3. The structure of these channels are not like other known channels. Chloride channel subunits contain between 1 and 12 transmembrane segments. Some members of this family are activated by voltage, while others are activated by Ca2+, extracellular ligands, and pH among other modulators.[2]

Commercial Applications[edit]

Some organic materials disrupt chloride channels in fleas, causing death. Selamectin is the active ingredient in Revolution, a topical insecticide and antihelminthic used on dogs and cats. Selamectin works by replacing glutamate which normally interacts with receptors that open chloride channels at muscle synapses found in parasites. Unlike glutamate, selamectin activates the chloride current without desensitization, thereby producing prolonged hyperpolarization and impaired muscle contraction.

Human genes[edit]

See also[edit]


  1. ^ Li WY, Wong FL, Tsai SN, Phang TH, Shao G, Lam HM (June 2006). "Tonoplast-located GmCLC1 and GmNHX1 from soybean enhance NaCl tolerance in transgenic bright yellow (BY)-2 cells". Plant Cell Environ. 29 (6): 1122–37. doi:10.1111/j.1365-3040.2005.01487.x. PMID 17080938. 
  2. ^ Suzuki M, Morita T, Iwamoto T (January 2006). "Diversity of Cl Channels". Cell. Mol. Life Sci. 63 (1): 12–24. doi:10.1007/s00018-005-5336-4. PMC 2792346. PMID 16314923. 

Further reading[edit]

External links[edit]

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Voltage gated chloride channel Provide feedback

This family of ion channels contains 10 or 12 transmembrane helices. Each protein forms a single pore. It has been shown that some members of this family form homodimers. In terms of primary structure, they are unrelated to known cation channels or other types of anion channels. Three ClC subfamilies are found in animals. ClC-1 (P35523) is involved in setting and restoring the resting membrane potential of skeletal muscle, while other channels play important parts in solute concentration mechanisms in the kidney [3]. These proteins contain two PF00571 domains.

Literature references

  1. Schmidt-Rose T, Jentsch TJ; , J Biol Chem 1997;272:20515-20521.: Reconstitution of functional voltage-gated chloride channels from complementary fragments of CLC-1. PUBMED:9252364 EPMC:9252364

  2. Zhang J, George AL Jr, Griggs RC, Fouad GT, Roberts J, Kwiecinski H, Connolly AM, Ptacek LJ; , Neurology 1996;47:993-998.: Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita. PUBMED:8857733 EPMC:8857733

  3. Mindell JA, Maduke M; , Genome Biol 2001;2:REVIEWS3003.: ClC chloride channels. PUBMED:11182894 EPMC:11182894

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001807

Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport [PUBMED:9046241].

The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata [PUBMED:2174129], and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl- channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl- channels is that some of the isoforms may function as Cl- channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains [PUBMED:2174129]. Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N- and C-termini residing in the cytoplasm [PUBMED:9207144].

A number of human disease-causing mutations have been identified in the genes encoding CLCs. Mutations in CLCN1, the gene encoding CLC-1, the major skeletal muscle Cl- channel, lead to both recessively and dominantly-inherited forms of muscle stiffness or myotonia [PUBMED:7581380]. Similarly, mutations in CLCN5, which encodes CLC-5, a renal Cl- channel, lead to several forms of inherited kidney stone disease [PUBMED:8559248]. These mutations have been demonstrated to reduce or abolish CLC function.

Gene Ontology

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Domain organisation

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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

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Curation and family details

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Seed source: wublastp P37020/1-588
Previous IDs: voltage_CLC;
Type: Family
Author: Bateman A
Number in seed: 139
Number in full: 7727
Average length of the domain: 337.70 aa
Average identity of full alignment: 23 %
Average coverage of the sequence by the domain: 63.73 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 23.8 23.8
Trusted cut-off 24.1 23.8
Noise cut-off 23.2 23.0
Model length: 355
Family (HMM) version: 15
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Species distribution

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There is 1 interaction for this family. More...



For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Voltage_CLC domain has been found. There are 57 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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