KCNK4 explained

Potassium channel subfamily K member 4 is a protein that in humans is encoded by the KCNK4 gene.^{[1] [2] [3]} KCNK4 protein channels are also called TRAAK channels.

Function

KNCK4 is a gene segment that encodes for the TRAAK (TWIK-related Arachidonic Acid-Stimulated K+) subfamily of mechanosensitive potassium channels. Potassium channels play a role in many cellular processes including action potential depolarization, muscle contraction, hormone secretion, osmotic regulation, and ion flow. The K_2P4.1 protein is a lipid-gated ion channel that belongs to the superfamily of potassium channel proteins containing two pore-forming P domains (K_2P). K_2P4.1 homodimerizes and functions as an outwardly rectifying channel. It is expressed primarily in neural tissues and is stimulated by membrane stretch and polyunsaturated fatty acids.

TRAAK channels are found in mammalian neurons and are part of a protein family of weakly inward rectifying potassium channels. This subfamily of potassium channels is mechanically gated. The C-terminal of TRAAK has a charged cluster that is important in maintaining the mechanosensitive properties of the channel.^[4]

TRAAK is only expressed in neuronal tissue, and can be found in the brain, spinal cord, and retina, which suggests that it has a function beyond mechanotransduction in terms of neuronal excitability.^[5] The highest levels of TRAAK expression are in the olfactory system, cerebral cortex, hippocampal formation, habenula, basal ganglia, and cerebellum.^[5] TRAAK channels are mechanically activated when there is a convex curvature in the membrane that alters the channel’s activity. TRAAK channels are thought to have a role in axonal pathfinding, growth cone motility, and neurite elongation, as well as possibly having a role in touch or pain detection.^{[6] [7]}

TRAAK channels play a critical role in the maintenance of the resting membrane potential in excitable cell types.^[8] More recently, TRAAK channels have been identified as an integral component of the nervous system, contributing to a variety of important biological functions such as: neurite migration, neurotransmission, and signal transduction across several sensory modalities.^[9] TRAAK and related mechanosensitive ion channels initiate these and other complex physiological processes by detecting asymmetrical pressure gradients generated across the inner and outer leaflets of the cell membrane, characterizing a rich profile of mechanical bilayer interactions.^[10] Furthermore, KCNK4 expression patterns the axonal segments of neurons in both central and peripheral nervous systems by inserting TRAAK membrane protein channels at the Nodes of Ranvier and allowing for saltatory conduction.^[11] The pathologies that are associated with improper KCNK4 expression such as Hirchsprung's Disease and FHEIG (facial dysmorphism, hypertrichosis, epilepsy, developmental/ID delay, and gingival overgrowth) syndrome, manifest accordingly as a constellation of neurological symptoms resulting from neuronal dysplasia.^{[12] [13]} Animal models containing known syndromic KCNK4 mutations have recapitulated these phenotypic abnormalities.^[14] High TRAAK channel density has also been implicated in the resulting cerebral ischemia following the event of a stroke.^[15]

See also

• Tandem pore domain potassium channel

Further reading

• Goldstein SA, Bockenhauer D, O'Kelly I, Zilberberg N . Potassium leak channels and the KCNK family of two-P-domain subunits . Nature Reviews. Neuroscience . 2 . 3 . 175–184 . March 2001 . 11256078 . 10.1038/35058574 . 9682396 .
• Chapman CG, Meadows HJ, Godden RJ, Campbell DA, Duckworth M, Kelsell RE, Murdock PR, Randall AD, Rennie GI, Gloger IS . 6 . Cloning, localisation and functional expression of a novel human, cerebellum specific, two pore domain potassium channel . Brain Research. Molecular Brain Research . 82 . 1–2 . 74–83 . October 2000 . 11042359 . 10.1016/S0169-328X(00)00183-2 . vanc .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–1795 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Meadows HJ, Chapman CG, Duckworth DM, Kelsell RE, Murdock PR, Nasir S, Rennie G, Randall AD . 6 . The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain K(+) channels TREK-1 and TRAAK . Brain Research . 892 . 1 . 94–101 . February 2001 . 11172753 . 10.1016/S0006-8993(00)03239-X . vanc . 37830674 .
• Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A . 6 . Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs . Genome Research . 11 . 3 . 422–435 . March 2001 . 11230166 . 311072 . 10.1101/gr.GR1547R . vanc .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Reports . 1 . 3 . 287–292 . September 2000 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 . vanc .
• Ozaita A, Vega-Saenz de Miera E . Cloning of two transcripts, HKT4.1a and HKT4.1b, from the human two-pore K+ channel gene KCNK4. Chromosomal localization, tissue distribution and functional expression . Brain Research. Molecular Brain Research . 102 . 1–2 . 18–27 . June 2002 . 12191490 . 10.1016/S0169-328X(02)00157-2 .
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . 6 . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16899–16903 . December 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . vanc . free . 2002PNAS...9916899M .
• Hillman RT, Green RE, Brenner SE . An unappreciated role for RNA surveillance . Genome Biology . 5 . 2 . R8 . 2005 . 14759258 . 395752 . 10.1186/gb-2004-5-2-r8 . free .
• Harinath S, Sikdar SK . Trichloroethanol enhances the activity of recombinant human TREK-1 and TRAAK channels . Neuropharmacology . 46 . 5 . 750–760 . April 2004 . 14996553 . 10.1016/j.neuropharm.2003.11.023 . 10938867 .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . 6 . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–2144 . October 2004 . 15489336 . 528930 . 10.1101/gr.2576704 . vanc .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . 6 . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Research . 16 . 1 . 55–65 . January 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 . vanc .
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . 6 . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415–D418 . January 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 . vanc .

Notes and References

1. Lesage F, Maingret F, Lazdunski M . Cloning and expression of human TRAAK, a polyunsaturated fatty acids-activated and mechano-sensitive K(+) channel . FEBS Letters . 471 . 2–3 . 137–140 . April 2000 . 10767409 . 10.1016/S0014-5793(00)01388-0 . 2000FEBSL.471..137L . 31793244 .
2. Goldstein SA, Bayliss DA, Kim D, Lesage F, Plant LD, Rajan S . International Union of Pharmacology. LV. Nomenclature and molecular relationships of two-P potassium channels . Pharmacological Reviews . 57 . 4 . 527–540 . December 2005 . 16382106 . 10.1124/pr.57.4.12 . 7356601 .
3. Web site: Entrez Gene: KCNK4 potassium channel, subfamily K, member 4.
4. Patel AJ, Honoré E, Lesage F, Fink M, Romey G, Lazdunski M . Inhalational anesthetics activate two-pore-domain background K+ channels . Nature Neuroscience . 2 . 5 . 422–426 . May 1999 . 10321245 . 10.1038/8084 . 23092576 .
5. Fink M, Lesage F, Duprat F, Heurteaux C, Reyes R, Fosset M, Lazdunski M . A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids . The EMBO Journal . 17 . 12 . 3297–3308 . June 1998 . 9628867 . 1170668 . 10.1093/emboj/17.12.3297 .
6. Vandorpe DH, Morris CE . Stretch activation of the Aplysia S-channel . The Journal of Membrane Biology . 127 . 3 . 205–214 . May 1992 . 1495087 . 10.1007/bf00231508 . 29622155 .
7. Maingret F, Fosset M, Lesage F, Lazdunski M, Honoré E . TRAAK is a mammalian neuronal mechano-gated K+ channel . The Journal of Biological Chemistry . 274 . 3 . 1381–1387 . January 1999 . 9880510 . 10.1074/jbc.274.3.1381 . free .
8. Brohawn SG, Wang W, Handler A, Campbell EB, Schwarz JR, MacKinnon R . The mechanosensitive ion channel TRAAK is localized to the mammalian node of Ranvier . eLife . 8 . e50403 . November 2019 . 31674909 . 6824864 . 10.7554/eLife.50403 . free .
9. Brohawn SG, Su Z, MacKinnon R . Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels . Proceedings of the National Academy of Sciences of the United States of America . 111 . 9 . 3614–3619 . March 2014 . 24550493 . 3948252 . 10.1073/pnas.1320768111 . free . 2014PNAS..111.3614B .
10. Clausen MV, Jarerattanachat V, Carpenter EP, Sansom MS, Tucker SJ . Asymmetric mechanosensitivity in a eukaryotic ion channel . Proceedings of the National Academy of Sciences of the United States of America . 114 . 40 . E8343–E8351 . October 2017 . 28923939 . 5635901 . 10.1073/pnas.1708990114 . 2017PNAS..114E8343C . free .
11. Kanda H, Ling J, Tonomura S, Noguchi K, Matalon S, Gu JG . TREK-1 and TRAAK Are Principal K⁺ Channels at the Nodes of Ranvier for Rapid Action Potential Conduction on Mammalian Myelinated Afferent Nerves . Neuron . 104 . 5 . 960–971.e7 . December 2019 . 31630908 . 6895425 . 10.1016/j.neuron.2019.08.042 .
12. O'Donnell AM, Nakamura H, Parekh B, Puri P . Decreased expression of TRAAK channels in Hirschsprung's disease: a possible cause of postoperative dysmotility . Pediatric Surgery International . 35 . 12 . 1431–1435 . December 2019 . 31542828 . 10.1007/s00383-019-04572-4 . 202718134 .
13. Gripp KW, Smithson SF, Scurr IJ, Baptista J, Majumdar A, Pierre G, Williams M, Henderson LB, Wentzensen IM, McLaughlin H, Leeuwen L, Simon ME, van Binsbergen E, Dinulos MB, Kaplan JD, McRae A, Superti-Furga A, Good JM, Kutsche K . 6 . Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K⁺ channelopathies . European Journal of Human Genetics . 29 . 9 . 1384–1395 . September 2021 . 33594261 . 8440610 . 10.1038/s41431-021-00818-9 .
14. Bauer CK, Calligari P, Radio FC, Caputo V, Dentici ML, Falah N, High F, Pantaleoni F, Barresi S, Ciolfi A, Pizzi S, Bruselles A, Person R, Richards S, Cho MT, Claps Sepulveda DJ, Pro S, Battini R, Zampino G, Digilio MC, Bocchinfuso G, Dallapiccola B, Stella L, Tartaglia M . 6 . Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome . American Journal of Human Genetics . 103 . 4 . 621–630 . October 2018 . 30290154 . 6174320 . 10.1016/j.ajhg.2018.09.001 .
15. Laigle C, Confort-Gouny S, Le Fur Y, Cozzone PJ, Viola A . Deletion of TRAAK potassium channel affects brain metabolism and protects against ischemia . PLOS ONE . 7 . 12 . e53266 . 2012-12-28 . 23285272 . 3532408 . 10.1371/journal.pone.0053266 . free . 2012PLoSO...753266L .