Calcium-dependent chloride channel

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TMEM16
Tmem16a EMD-3860.png
Cartoon representation of a mTMEM16A chloride channel based on a cryoelectron microscopy reconstruction. [1]
Identifiers
SymbolApoctamin
Pfam PF04547
InterPro IPR032394
TCDB 1.A.17
OPM superfamily 369
Membranome 219

The Calcium-Dependent Chloride Channel (Ca-ClC) proteins (or calcium-activated chloride channels (CaCCs), [2] are heterogeneous groups of ligand-gated ion channels for chloride that have been identified in many epithelial and endothelial cell types as well as in smooth muscle cells. They include proteins from several structurally different families: chloride channel accessory (CLCA), [3] bestrophin (BEST), [4] [5] and calcium-dependent chloride channel anoctamin (ANO or TMEM16) channels [4] [5] [6] [7] ANO1 is highly expressed in human gastrointestinal interstitial cells of Cajal, which are proteins which serve as intestinal pacemakers for peristalsis. [6] In addition to their role as chloride channels some CLCA proteins function as adhesion molecules and may also have roles as tumour suppressors. [8] These eukaryotic proteins are "required for normal electrolyte and fluid secretion, olfactory perception, and neuronal and smooth muscle excitability" in animals. [9] [10] Members of the Ca-CIC family are generally 600 to 1000 amino acyl residues (aas) in length and exhibit 7 to 10 transmembrane segments (TMSs).

Contents

Function

Tmc1 and Tmc2 (TC#s 1.A.17.4.6 and 1.A.17.4.1, respectively) may play a role in hearing and are required for normal function of cochlear hair cells, possibly as Ca2+ channels or Ca2+ channel subunits (see also family TC# 1.A.82). [11] Mice lacking both channels lack hair cell mechanosensory potentials. [12] There are 8 members of this family in humans, 1 in Drosophila and 2 in C. elegans . One of the latter two is expressed in mechanoreceptors. [13] Tmc1 is a sodium-sensitive cation channel required for salt (Na+) chemosensation in C. elegans "where it is required for salt-evoked neuronal activity and behavioural avoidance of high concentrations of NaCl". [14]

TMEM16A is over-expressed in several tumor types. The role of TMEM16A in gliomas and the potential underlying mechanisms were analyzed by Liu et al. 2014. Knockdown of TMEM16A suppressed cell proliferation, migration and invasion. [15]

The reactions believed to be catalyzed by channels of the Ca-ClC family are: [16]

Cl− (out) ⇌ Cl− (in)

and

Cations (e.g., Ca2+) (out) ⇌ Cations (e.g., Ca2+) (in)

In humans

CaCCs that are known to occur in humans include:

See also

Notes

  1. ↑ The anoctamins are only expressed in eukaryotes, with 10 members in vertebrates. [7] Although all anoctamins are calcium-activated, not all members of this family are ion channels like ANO1; some are phospholipid scramblases. [7] ANO1 was the first anoctamin discovered, with three research groups independently identifying it in 2008. [7] A single protein homologue to the vertebrate anoctamins has been found in fungi and yeast, Aspergillus fumigatus and Saccharomyces cerevisiae , respsectively. [7]

Related Research Articles

Ion channel

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

Olfactory receptor neuron

An olfactory receptor neuron (ORN), also called an olfactory sensory neuron (OSN), is a sensory neuron within the olfactory system.

Calcium release-activated channels (CRAC) are specialized plasma membrane Ca2+ ion channels. When calcium ions (Ca2+) are depleted from the endoplasmic reticulum (a major store of Ca2+) of mammalian cells, the CRAC channel is activated to slowly replenish the level of calcium in the endoplasmic reticulum. The Ca2+ Release-activated Ca2+ (CRAC) Channel (CRAC-C) Family (TC# 1.A.52) is a member of the Cation Diffusion Facilitator (CDF) Superfamily. These proteins typically have between 4 and 6 transmembrane α-helical spanners (TMSs). The 4 TMS CRAC channels arose by loss of 2TMSs from 6TMS CDF carriers, an example of 'reverse' evolution'.

Voltage-gated ion channel type of ion channel transmembrane protein

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels. They have a crucial role in excitable cells such as neuronal and muscle tissues, allowing a rapid and co-ordinated depolarization in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. Voltage-gated ion-channels are usually ion-specific, and channels specific to sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl−) ions have been identified. The opening and closing of the channels are triggered by changing ion concentration, and hence charge gradient, between the sides of the cell membrane.

Chloride channel

Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels have been characterized in humans.

Calcium-activated potassium channels are potassium channels gated by calcium, or that are structurally or phylogenetically related to calcium gated channels. They were first discovered in 1958 by Gardos who saw that Calcium levels inside of a cell could affect the permeability of potassium through that cell membrane. Then in 1970, Meech was the first to observe that intracellular calcium could trigger potassium currents. In humans they are divided into three subtypes: large conductance or BK channels, which have very high conductance which range from 100 to 300 pS, intermediate conductance or IK channels, with intermediate conductance ranging from 25 to 100 pS, and small conductance or SK channels with small conductances from 2-25 pS.

STIM1

Stromal interaction molecule 1 is a protein that in humans is encoded by the STIM1 gene. STIM1 has a single transmembrane domain, and is localized to the endoplasmic reticulum, and to a lesser extent to the plasma membrane.

CLCN5

The CLCN5 gene encodes the chloride channel Cl-/H+ exchanger ClC-5. ClC-5 is mainly expressed in the kidney, in particular in proximal tubules where it participates to the uptake of albumin and low-molecular-weight proteins, which is one of the principal physiological role of proximal tubular cells. Mutations in the CLCN5 gene cause an X-linked recessive nephropathy named Dent disease characterized by excessive urinary loss of low-molecular-weight proteins and of calcium (hypercalciuria), nephrocalcinosis and nephrolithiasis.

Bestrophin 1

Bestrophin-1 (Best1) is a protein that, in humans, is encoded by the BEST1 gene.

KCNN4

Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4, also known as KCNN4, is a human gene encoding the KCa3.1 protein.

CLCA1

Chloride channel accessory 1 is a protein that in humans is encoded by the CLCA1 gene.

Ca<sub>v</sub>1.3

Calcium channel, voltage-dependent, L type, alpha 1D subunit is a protein that in humans is encoded by the CACNA1D gene. Cav1.3 channels belong to the Cav1 family, which form L-type calcium currents and are sensitive to selective inhibition by dihydropyridines (DHP).

CLCA2

Chloride channel accessory 2 is a protein that in humans is encoded by the CLCA2 gene.

CLCA3

Chloride channel accessory 3, also known as CLCA3, is a protein which in humans is encoded by the CLCA3P pseudogene. The protein encoded by this gene is a chloride channel. According to the HGNC, this protein is not expressed in humans but is in certain other species such as mouse. However, some conflicting reports state that human cells produce and glycosylate this protein.

ANO1

Anoctamin-1 (ANO1) also known as Transmembrane member 16A (TMEM16A) is a protein that, in humans, is encoded by the ANO1 gene. Anoctamin-1 is a voltage-gated calcium-activated anion channel, which acts as a chloride channel and a bicarbonate channel. additionally Anoctamin-1 is apical iodide channel. It is expressed in smooth muscle, epithelial cells, vomeronasal neurons, olfactory sustentacular cells, and is highly expressed in human interstitial cells of Cajal (ICC) throughout the gastrointestinal tract.

Gating (electrophysiology)

In electrophysiology, the term gating refers to the opening (activation) or closing of ion channels. This change in conformation is a response to changes in transmembrane voltage.

ANO3 is a gene that in humans is located on chromosome 11 and encodes the protein anoctamin 3. It belongs to a family of genes (ANO1–ANO10) that appear to encode calcium-activated chloride channels.

Anoctamin 6

Anoctamin 6 is a protein that in humans is encoded by the ANO6 gene.

ANO5

Anoctamin 5 (ANO5) is a protein that in humans is encoded by the ANO5 gene.

References

  1. ↑ PDB: 5oyb ​; Paulino C, Kalienkova V, Lam A, Neldner Y, Dutzler R (December 2017). "Activation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EM" (PDF). Nature. 552 (7685): 421–425. Bibcode:2017Natur.552..421P. doi:10.1038/nature24652. PMID   29236691. S2CID   4457894.
  2. ↑ Hartzell C, Putzier I, Arreola J (March 2005). "Calcium-activated chloride channels". Annual Review of Physiology. 67: 719–58. doi:10.1146/annurev.physiol.67.032003.154341. PMID   15709976. Closed Access logo transparent.svg
  3. ↑ "CLCA1 chloride channel accessory 1 [Homo sapiens (human)]". Gene . National Center for Biotechnology Information. 13 January 2015.
  4. 1 2 Kunzelmann K, Kongsuphol P, Chootip K, Toledo C, Martins JR, Almaca J, Tian Y, Witzgall R, Ousingsawat J, Schreiber R (January 2011). "Role of the Ca2+ -activated Cl- channels bestrophin and anoctamin in epithelial cells". Biological Chemistry. 392 (1–2): 125–34. doi:10.1515/BC.2011.010. PMID   21194364. S2CID   24285022.
  5. 1 2 Kunzelmann K, Kongsuphol P, Aldehni F, Tian Y, Ousingsawat J, Warth R, Schreiber R (October 2009). "Bestrophin and TMEM16-Ca(2+) activated Cl(-) channels with different functions". Cell Calcium. 46 (4): 233–41. doi:10.1016/j.ceca.2009.09.003. PMID   19783045.
  6. 1 2 Sanders KM, Zhu MH, Britton F, Koh SD, Ward SM (February 2012). "Anoctamins and gastrointestinal smooth muscle excitability". Experimental Physiology. 97 (2): 200–6. doi:10.1113/expphysiol.2011.058248. PMC   3272164 . PMID   22002868. Open Access logo PLoS transparent.svg
  7. ↑ Brunner JD, Lim NK, Schenck S, Duerst A, Dutzler R (December 2014). "X-ray structure of a calcium-activated TMEM16 lipid scramblase". Nature. 516 (7530): 207–12. Bibcode:2014Natur.516..207B. doi:10.1038/nature13984. PMID   25383531. S2CID   1396768.
  8. ↑ Evans SR, Thoreson WB, Beck CL (October 2004). "Molecular and functional analyses of two new calcium-activated chloride channel family members from mouse eye and intestine". The Journal of Biological Chemistry. 279 (40): 41792–800. doi: 10.1074/jbc.M408354200 . PMC   1383427 . PMID   15284223.
  9. ↑ Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJ (October 2008). "TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity". Science. 322 (5901): 590–4. Bibcode:2008Sci...322..590C. doi:10.1126/science.1163518. PMID   18772398. S2CID   52870095.
  10. ↑ Pang C, Yuan H, Ren S, Chen Y, An H, Zhan Y (1 January 2014). "TMEM16A/B associated CaCC: structural and functional insights". Protein and Peptide Letters. 21 (1): 94–9. doi:10.2174/09298665113206660098. PMID   24151904.
  11. ↑ Kim KX, Fettiplace R (January 2013). "Developmental changes in the cochlear hair cell mechanotransducer channel and their regulation by transmembrane channel-like proteins". The Journal of General Physiology. 141 (1): 141–8. doi:10.1085/jgp.201210913. PMC   3536526 . PMID   23277480.
  12. ↑ Kawashima Y, Géléoc GS, Kurima K, Labay V, Lelli A, Asai Y, Makishima T, Wu DK, Della Santina CC, Holt JR, Griffith AJ (December 2011). "Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes". The Journal of Clinical Investigation. 121 (12): 4796–809. doi:10.1172/JCI60405. PMC   3223072 . PMID   22105175.
  13. ↑ Smith CJ, Watson JD, Spencer WC, O'Brien T, Cha B, Albeg A, Treinin M, Miller DM (September 2010). "Time-lapse imaging and cell-specific expression profiling reveal dynamic branching and molecular determinants of a multi-dendritic nociceptor in C. elegans". Developmental Biology. 345 (1): 18–33. doi:10.1016/j.ydbio.2010.05.502. PMC   2919608 . PMID   20537990.
  14. ↑ Chatzigeorgiou M, Bang S, Hwang SW, Schafer WR (February 2013). "tmc-1 encodes a sodium-sensitive channel required for salt chemosensation in C. elegans". Nature. 494 (7435): 95–99. Bibcode:2013Natur.494...95C. doi:10.1038/nature11845. PMC   4021456 . PMID   23364694.
  15. ↑ Liu J, Liu Y, Ren Y, Kang L, Zhang L (March 2014). "Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-κB signaling pathway". Molecular Medicine Reports. 9 (3): 1068–74. doi: 10.3892/mmr.2014.1888 . PMID   24401903.
  16. ↑ "1.A.17 The Calcium-Dependent Chloride Channel (Ca-ClC) Family". TCDB. Retrieved 16 April 2016.
  17. 1 2 "Calcium activated chloride channel". IUPHAR/BPS Guide to Pharmacology. Retrieved 7 October 2015.

Further reading

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