This article is about the human protein3. For the Finnish Steam Locomotive, see VR Class Sk3. For SK-3, the Russian spaceport, see Plesetsk Cosmodrome Site 43. For the 1930s air racer, see Folkerts SK-3. For SK3, the U.S Navy rate and rank, see Storekeeper.
SK3 (small conductance calcium-activated potassium channel 3) also known as KCa2.3 is a protein that in humans is encoded by the KCNN3gene.[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 (encoded by the KCNN1, 2 and 3 genes respectively), which share a 60-70% sequence identity.[3] 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.
The expression level of KCNN3 is dependent on hormonal regulation, particularly by the sex hormoneestrogen. Estrogen not only enhances transcription of the KCNN3 gene, but also affects the activity of KCa2.3 channels on the cell membrane. In GABAergicpreoptic area neurons, estrogen enhanced the ability of α1 adrenergic receptors to inhibit KCa2.3 activity, increasing cell excitability.[6] 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.[3] The influence of estrogen on KCa2.3 has also been established in the hypothalamus, uterine and skeletal muscle.[6]
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.[7] 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.
↑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. PMID9491810.
↑ 2.02.1Wei 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. PMID16382103.
↑ 3.03.13.23.3Chen 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. PMID15127180.
↑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. doi:10.1126/science.273.5282.1709. PMID8781233.
↑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. PMID17584055.
↑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. PMID12805243.
↑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. PMID15389773.
↑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. PMID16157352.
↑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. PMID12808432.
↑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. PMID12875918.
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. PMID12898569.
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. PMID16393881.
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. PMID17061167.
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. PMID12497613.
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. PMID12960745.
Zhou Z, Jiang DJ, Jia SJ, et al. (2007). "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. PMID17869187.
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. PMID15389773.
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. PMID14638680.
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. doi:10.1016/S0022-3468(03)00138-6. PMID12778407.
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. PMID16086287.
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. PMID17101631.
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. PMID12808432.
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. PMID14559917.
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. PMID19058789.