KCNN3
Identifiers
AliasesKCNN3, KCa2.3, SK3, SKCA3, hSK3, potassium calcium-activated channel subfamily N member 3, ZLS3
External IDsOMIM: 602983 MGI: 2153183 HomoloGene: 20516 GeneCards: KCNN3
Orthologs
SpeciesHumanMouse
Entrez

3782

140493

Ensembl

ENSG00000143603

ENSMUSG00000000794

UniProt

Q9UGI6

P58391

RefSeq (mRNA)

NM_170782
NM_001204087
NM_002249
NM_001365837
NM_001365838

NM_080466

RefSeq (protein)

NP_001191016
NP_002240
NP_740752
NP_001352766
NP_001352767

NP_536714

Location (UCSC)Chr 1: 154.7 – 154.87 MbChr 3: 89.43 – 89.58 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

SK3 (small conductance calcium-activated potassium channel 3) also known as KCa2.3 is a protein that in humans is encoded by the KCNN3 gene.[5][6]

SK3 is a small-conductance calcium-activated potassium channel partly responsible for the calcium-dependent after hyperpolarisation current (IAHP). It belongs to a family of channels known as small-conductance potassium channels, which consists of three members – SK1, SK2 and SK3 (encoded by the KCNN1, 2 and 3 genes respectively), which share a 60-70% sequence identity.[7] These channels have acquired a number of alternative names, however a NC-IUPHAR has recently achieved consensus on the best names, KCa2.1 (SK1), KCa2.2 (SK2) and KCa2.3 (SK3).[6] Small conductance channels are responsible for the medium and possibly the slow components of the IAHP.

Structure

KCa2.3 contains 6 transmembrane domains, a pore-forming region, and intracellular N- and C- termini[7][8] and is readily blocked by apamin. The gene for KCa2.3, KCNN3, is located on chromosome 1q21.

Expression

KCa2.3 is found in the central nervous system (CNS), muscle, liver, pituitary, prostate, kidney, pancreas and vascular endothelium tissues.[9] KCa2.3 is most abundant in regions of the brain, but has also been found to be expressed in significant levels in many other peripheral tissues, particularly those rich in smooth muscle, including the rectum, corpus cavernosum, colon, small intestine and myometrium.[7]

The expression level of KCNN3 is dependent on hormonal regulation, particularly by the sex hormone estrogen. Estrogen not only enhances transcription of the KCNN3 gene, but also affects the activity of KCa2.3 channels on the cell membrane. In GABAergic preoptic area neurons, estrogen enhanced the ability of α1 adrenergic receptors to inhibit KCa2.3 activity, increasing cell excitability.[10] Links between hormonal regulation of sex organ function and KCa2.3 expression have been established. The expression of KCa2.3 in the corpus cavernosum in patients undergoing estrogen treatment as part of gender reassignment surgery was found to be increased up to 5-fold.[7] The influence of estrogen on KCa2.3 has also been established in the hypothalamus, uterine and skeletal muscle.[10]

Physiology

KCa2.3 channels play a major role in human physiology, particularly in smooth muscle relaxation. The expression level of KCa2.3 channels in the endothelium influences arterial tone by setting arterial smooth muscle membrane potential. The sustained activity of KCa2.3 channels induces a sustained hyperpolarisation of the endothelial cell membrane potential, which is then carried to nearby smooth muscle through gap junctions.[11] Blocking the KCa2.3 channel or suppressing KCa2.3 expression causes a greatly increased tone in resistance arteries, producing an increase in peripheral resistance and blood pressure.

Pathology

Mutations in KCa2.3 are suspected to be a possible underlying cause for several neurological disorders, including schizophrenia, bipolar disorder, Alzheimer's disease, anorexia nervosa and ataxia[12][13][14] as well as myotonic muscular dystrophy.[15]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000143603 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000000794 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Chandy KG, Fantino E, Wittekindt O, Kalman K, Tong LL, Ho TH, Gutman GA, Crocq MA, Ganguli R, Nimgaonkar V, Morris-Rosendahl DJ, Gargus JJ (January 1998). "Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder?". Mol. Psychiatry. 3 (1): 32–7. doi:10.1038/sj.mp.4000353. PMID 9491810.
  6. 1 2 Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S, Wulff H (December 2005). "International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels". Pharmacol. Rev. 57 (4): 463–72. doi:10.1124/pr.57.4.9. PMID 16382103. S2CID 8290401.
  7. 1 2 3 4 Chen MX, Gorman SA, Benson B, Singh K, Hieble JP, Michel MC, Tate SN, Trezise DJ (June 2004). "Small and intermediate conductance Ca(2+)-activated K+ channels confer distinctive patterns of distribution in human tissues and differential cellular localisation in the colon and corpus cavernosum". Naunyn Schmiedebergs Arch. Pharmacol. 369 (6): 602–15. doi:10.1007/s00210-004-0934-5. PMID 15127180. S2CID 6309146.
  8. ↑ Köhler M, Hirschberg B, Bond CT, Kinzie JM, Marrion NV, Maylie J, Adelman JP (September 1996). "Small-conductance, calcium-activated potassium channels from mammalian brain". Science. 273 (5282): 1709–14. Bibcode:1996Sci...273.1709K. doi:10.1126/science.273.5282.1709. PMID 8781233. S2CID 11603552.
  9. ↑ Wulff H, Kolski-Andreaco A, Sankaranarayanan A, Sabatier JM, Shakkottai V (2007). "Modulators of small- and intermediate-conductance calcium-activated potassium channels and their therapeutic indications". Curr. Med. Chem. 14 (13): 1437–57. doi:10.2174/092986707780831186. PMID 17584055. S2CID 13139192.
  10. 1 2 Jacobson D, Pribnow D, Herson PS, Maylie J, Adelman JP (April 2003). "Determinants contributing to estrogen-regulated expression of SK3". Biochem. Biophys. Res. Commun. 303 (2): 660–8. doi:10.1016/S0006-291X(03)00408-X. PMID 12659870.
  11. ↑ Taylor MS, Bonev AD, Gross TP, Eckman DM, Brayden JE, Bond CT, Adelman JP, Nelson MT (July 2003). "Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure". Circ. Res. 93 (2): 124–31. doi:10.1161/01.RES.0000081980.63146.69. PMID 12805243.
  12. ↑ Koronyo-Hamaoui M, Gak E, Stein D, Frisch A, Danziger Y, Leor S, Michaelovsky E, Laufer N, Carel C, Fennig S, Mimouni M, Apter A, Goldman B, Barkai G, Weizman A (November 2004). "CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: a case-control study of female patients and several ethnic groups in the Israeli Jewish population". Am. J. Med. Genet. B Neuropsychiatr. Genet. 131B (1): 76–80. doi:10.1002/ajmg.b.20154. PMID 15389773. S2CID 24415070.
  13. ↑ Koronyo-Hamaoui M, Frisch A, Stein D, Denziger Y, Leor S, Michaelovsky E, Laufer N, Carel C, Fennig S, Mimouni M, Ram A, Zubery E, Jeczmien P, Apter A, Weizman A, Gak E (2007). "Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca(2+)-activated K+ channel to genetic predisposition to anorexia nervosa". J Psychiatr Res. 41 (1–2): 160–7. doi:10.1016/j.jpsychires.2005.07.010. PMID 16157352.
  14. ↑ Tomita H, Shakkottai VG, Gutman GA, Sun G, Bunney WE, Cahalan MD, Chandy KG, Gargus JJ (May 2003). "Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia". Mol. Psychiatry. 8 (5): 524–35, 460. doi:10.1038/sj.mp.4001271. PMID 12808432. S2CID 1569495.
  15. ↑ Kimura T, Takahashi MP, Fujimura H, Sakoda S (August 2003). "Expression and distribution of a small-conductance calcium-activated potassium channel (SK3) protein in skeletal muscles from myotonic muscular dystrophy patients and congenital myotonic mice". Neurosci. Lett. 347 (3): 191–5. doi:10.1016/S0304-3940(03)00638-4. PMID 12875918. S2CID 11678544.

Further reading

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