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Gene Review

KCNK6  -  potassium channel, two pore domain...

Homo sapiens

Synonyms: Inward rectifying potassium channel protein TWIK-2, K2p6.1, KCNK8, Potassium channel subfamily K member 6, TOSS, ...
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Disease relevance of KCNK6

  • Both STS and linkage maps established KCNK6 as a positional candidate gene for DFNA4, a form of autosomal dominant nonsyndromic hereditary hearing loss [1].

High impact information on KCNK6

  • In a physiological K(+) gradient, TWIK-2 is half inhibited by 0.1 mm Ba(2+), quinine, and quinidine [2].
  • We cloned human and rat TWIK-2 and expressed this novel 2P domain K(+) channel in transiently transfected COS cells [2].
  • TWIK-2 is highly expressed in the gastrointestinal tract, the vasculature, and the immune system [2].
  • Finally, cysteine 53 in the M1P1 external loop is required for functional expression of TWIK-2 but is not critical for subunit self-assembly [2].
  • Deletions, mutations, and chimera constructions suggest that KCNK6 is not an intracellular channel but rather a subunit that needs to associate with a partner, which remains to be discovered, in order to reach the plasma membrane [3].

Biological context of KCNK6

  • We have cloned a new member of this family, TWIK-2, from a human brain cDNA library [4].
  • KCNK6 encodes a tandem pore domain potassium channel, TWIK-2, that maps to chromosome 19 [1].
  • Despite the same predicted topology, there is a relatively low sequence homology between TWIK-originated similarity sequence and other members of the mammalian tandem pore domain K+ channel subunit family group [5].
  • Genomic structure of TWIK-2 was subsequently determined and shown to consist of three coding exons with splice acceptor and donor sites in accordance with the consensus GT-AG rule [1].

Anatomical context of KCNK6

  • Although KCNK6 is able to dimerize as other functional two-P domain K+ channels when it is expressed in COS-7 cells, it remains in the endoplasmic reticulum and is unable to generate ionic channel activity [3].
  • Human TWIK-2 expressed heterologously in Xenopus oocytes is a non-inactivating weak inward rectifier with channel properties similar to TWIK-1 [4].
  • Northern blot analysis reveals the expression of TWIK-2 in all human tissues assayed except skeletal muscle [4].
  • Identification of Twik-2 expression in the mouse cochlea was initially established via RT-PCR assay of cochlear RNA [1].
  • Nevertheless, expression of Twik-2 within the stria vascularis suggests a potential role for this protein as one of the terminal components of the potassium ion-recycling pathway that contributes toward its reabsorption into the endolymph [1].

Other interactions of KCNK6

  • Two separate DFNA4 families were screened for KCNK6 sequence alterations [1].
  • Pharmacologically, TWIK-2 channels are distinct from TWIK-1 channels in their response to quinidine, quinine, and barium [4].

Analytical, diagnostic and therapeutic context of KCNK6


  1. Genomic structure, cochlear expression, and mutation screening of KCNK6, a candidate gene for DFNA4. Mhatre, A.N., Li, J., Chen, A.F., Yost, C.S., Smith, R.J., Kindler, C.H., Lalwani, A.K. J. Neurosci. Res. (2004) [Pubmed]
  2. TWIK-2, an inactivating 2P domain K+ channel. Patel, A.J., Maingret, F., Magnone, V., Fosset, M., Lazdunski, M., Honoré, E. J. Biol. Chem. (2000) [Pubmed]
  3. Cloning of a new mouse two-P domain channel subunit and a human homologue with a unique pore structure. Salinas, M., Reyes, R., Lesage, F., Fosset, M., Heurteaux, C., Romey, G., Lazdunski, M. J. Biol. Chem. (1999) [Pubmed]
  4. TWIK-2, a new weak inward rectifying member of the tandem pore domain potassium channel family. Chavez, R.A., Gray, A.T., Zhao, B.B., Kindler, C.H., Mazurek, M.J., Mehta, Y., Forsayeth, J.R., Yost, C.S. J. Biol. Chem. (1999) [Pubmed]
  5. Identification and cloning of TWIK-originated similarity sequence (TOSS): a novel human 2-pore K+ channel principal subunit. Pountney, D.J., Gulkarov, I., Vega-Saenz de Miera, E., Holmes, D., Saganich, M., Rudy, B., Artman, M., Coetzee, W.A. FEBS Lett. (1999) [Pubmed]
  6. Assignment of KCNK6 encoding the human weak inward rectifier potassium channel TWIK-2 to chromosome band 19q13.1 by radiation hybrid mapping. Gray, A.T., Kindler, C.H., Sampson, E.R., Yost, C.S. Cytogenet. Cell Genet. (1999) [Pubmed]
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