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potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3
Available structures
1qx7, 1g4y, 1kkd
Identifiers
Symbols KCNN3; SKCA3; hSK3; SK3
External IDs OMIM602983 MGI2153183 HomoloGene20516 IUPHAR: KCa2.3 GeneCards: KCNN3 Gene
Orthologs
Species Human Mouse
Entrez 3782 140493
Ensembl ENSG00000143603 ENSMUSG00000000794
UniProt Q9UGI6 Q3UUY9
RefSeq (mRNA) NM_002249 NM_080466
RefSeq (protein) NP_740752 NP_536714
Location (UCSC) Chr 1:
154.68 - 154.84 Mb
Chr 3:
89.32 - 89.47 Mb
PubMed search [1] [2]

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 (KCNN1, 2 and 3 respectively), which share a 60-70% sequence identity.[1] 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).[2] Small conductance channels are responsible for the medium and possibly the slow components of the IAHP.

Contents

Structure

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

Expression

KCa2.3 is found in almost every tissue in the human body, with exceptions being the pancreas, placenta, adipose tissue, liver, prostate and skin.[1] 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 myometirum.[1]

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 POA neurons, estrogen enhanced the ability of α1 adrenergic receptors to inhibit KCa2.3 activity, increasing cell excitability.[4] 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.[1] The influence of estrogen on KCa2.3 has also been established in the hypothalamus, uterine and skeletal muscle.[4]

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.[5] 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[6][7][8] as well as myotonic muscular dystrophy.[9]

References

  1. ^ a b c d e 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.  
  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.  
  3. ^ 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 (journal) 273 (5282): 1709–14. doi:10.1126/science.273.5282.1709. PMID 8781233.  
  4. ^ a b 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.  
  5. ^ 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.  
  6. ^ 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.  
  7. ^ 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.  
  8. ^ 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.  
  9. ^ 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.  

Further reading

  • Glatt SJ, Faraone SV, Tsuang MT (2003). "CAG-repeat length in exon 1 of KCNN3 does not influence risk for schizophrenia or bipolar disorder: a meta-analysis of association studies.". Am. J. Med. Genet. B Neuropsychiatr. Genet. 121B (1): 14–20. doi:10.1002/ajmg.b.20048. PMID 12898569.  
  • Ivković M, Ranković V, Tarasjev A, et al. (2006). "Schizophrenia and polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene in Serbian population.". Int. J. Neurosci. 116 (2): 157–64. doi:10.1080/00207450341514. PMID 16393881.  
  • Uhl GR, Liu QR, Drgon T, et al. (2008). "Molecular genetics of successful smoking cessation: convergent genome-wide association study results.". Arch. Gen. Psychiatry 65 (6): 683–93. doi:10.1001/archpsyc.65.6.683. PMID 18519826.  
  • Curtain R, Sundholm J, Lea R, et al. (2005). "Association analysis of a highly polymorphic CAG Repeat in the human potassium channel gene KCNN3 and migraine susceptibility.". BMC Med. Genet. 6: 32. doi:10.1186/1471-2350-6-32. PMID 16162291.  
  • Dagle JM, Lepp NT, Cooper ME, et al. (2009). "Determination of genetic predisposition to patent ductus arteriosus in preterm infants.". Pediatrics 123 (4): 1116–23. doi:10.1542/peds.2008-0313. PMID 19336370.  
  • Rinaldi F, Botta A, Vallo L, et al. (2008). "Analysis of Single Nucleotide Polymorphisms (SNPs) of the small-conductance calcium activated potassium channel (SK3) gene as genetic modifier of the cardiac phenotype in myotonic dystrophy type 1 patients.". Acta Myol 27: 82–9. PMID 19472917.  
  • Decimo I, Roncarati R, Grasso S, et al. (2006). "SK3 trafficking in hippocampal cells: the role of different molecular domains.". Biosci. Rep. 26 (6): 399–412. doi:10.1007/s10540-006-9029-5. PMID 17061167.  
  • Laurent C, Niehaus D, Bauché S, et al. (2003). "CAG repeat polymorphisms in KCNN3 (HSKCa3) and PPP2R2B show no association or linkage to schizophrenia.". Am. J. Med. Genet. B Neuropsychiatr. Genet. 116B (1): 45–50. doi:10.1002/ajmg.b.10797. PMID 12497613.  
  • Ritsner M, Amir S, Koronyo-Hamaoui M, et al. (2003). "Association study of CAG repeats in the KCNN3 gene in Israeli patients with major psychosis.". Psychiatr. Genet. 13 (3): 143–50. doi:10.1097/01.ypg.0000066965.80715.f4. PMID 12960745.  
  • Gao Y, Chotoo CK, Balut CM, et al. (2008). "Role of S3 and S4 transmembrane domain charged amino acids in channel biogenesis and gating of KCa2.3 and KCa3.1.". J. Biol. Chem. 283 (14): 9049–59. doi:10.1074/jbc.M708022200. PMID 18227067.  
  • Zhou Z, Jiang DJ, Jia SJ, et al.. "Down-regulation of endogenous nitric oxide synthase inhibitors on endothelial SK3 expression.". Vascul. Pharmacol. 47 (5-6): 265–71. doi:10.1016/j.vph.2007.08.003. PMID 17869187.  
  • Koronyo-Hamaoui M, Gak E, Stein D, et al. (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.  
  • Kolski-Andreaco A, Tomita H, Shakkottai VG, et al. (2004). "SK3-1C, a dominant-negative suppressor of SKCa and IKCa channels.". J. Biol. Chem. 279 (8): 6893–904. doi:10.1074/jbc.M311725200. PMID 14638680.  
  • Wei AD, Gutman GA, Aldrich R, et al. (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.  
  • Piotrowska AP, Solari V, Puri P (2003). "Distribution of Ca2+-activated K channels, SK2 and SK3, in the normal and Hirschsprung's disease bowel.". J. Pediatr. Surg. 38 (6): 978–83. PMID 12778407.  
  • Hong XH, Xu CT, Yang Q, Wu CR (2005). "[Transmission disequilibrium analysis of 1137-1140 Del GTGA frameshift mutation within the KCNN3 gene and schizophrenia based on family trios]". Zhonghua Yi Xue Yi Chuan Xue Za Zhi 22 (4): 441–3. PMID 16086287.  
  • Rhodes JD, Monckton DG, McAbney JP, et al. (2006). "Increased SK3 expression in DM1 lens cells leads to impaired growth through a greater calcium-induced fragility.". Hum. Mol. Genet. 15 (24): 3559–68. doi:10.1093/hmg/ddl432. PMID 17101631.  
  • Tomita H, Shakkottai VG, Gutman GA, et al. (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.  
  • Monaghan AS, Benton DC, Bahia PK, et al. (2004). "The SK3 subunit of small conductance Ca2+-activated K+ channels interacts with both SK1 and SK2 subunits in a heterologous expression system.". J. Biol. Chem. 279 (2): 1003–9. doi:10.1074/jbc.M308070200. PMID 14559917.  
  • de Krom M, Staal WG, Ophoff RA, et al. (2009). "A common variant in DRD3 receptor is associated with autism spectrum disorder.". Biol. Psychiatry 65 (7): 625–30. doi:10.1016/j.biopsych.2008.09.035. PMID 19058789.  
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