View source for SK3

{{PBB|geneid=3782}}

'''SK3''' is a small-conductance [[calcium-activated potassium channel]] partly responsible for the [[calcium]]-dependent [[after hyperpolarisation]] current (I<sub>AHP</sub>). It belongs to a family of channels known as [[SK channel|small-conductance potassium channel]]s, which consists of three members – SK1, SK2 and SK3 (KCNN1, 2 and 3 respectively), which share a 60-70% [[sequence identity]].<ref name="pmid15127180">{{cite journal | author = Chen MX, Gorman SA, Benson B, Singh K, Hieble JP, Michel MC, Tate SN, Trezise DJ | title = 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 | journal = Naunyn Schmiedebergs Arch. Pharmacol. | volume = 369 | issue = 6 | pages = 602–15 | year = 2004 | month = June | pmid = 15127180 | doi = 10.1007/s00210-004-0934-5 | url =  }}</ref> These channels have acquired a number of alternative names, however a NC-[[IUPHAR]] has recently achieved consensus on the best names, '''K<sub>Ca</sub>2.1''' (SK1), '''K<sub>Ca</sub>2.2''' (SK2) and '''K<sub>Ca</sub>2.3''' (SK3).<ref name="pmid16382103">{{cite journal | author = Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S, Wulff H | title = International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels | journal = Pharmacol. Rev. | volume = 57 | issue = 4 | pages = 463–72 | year = 2005 | month = December | pmid = 16382103 | doi = 10.1124/pr.57.4.9 | url =  }}</ref> Small conductance channels are responsible for the medium and possibly the slow components of the I<sub>AHP</sub>.

==Structure==
K<sub>Ca</sub>2.3 contains 6 [[transmembrane domain]]s, a pore-forming region, and intracellular [[N-terminus|N]]- and [[C-terminus|C- termini]]<ref name="pmid8781233">{{cite journal | author = Köhler M, Hirschberg B, Bond CT, Kinzie JM, Marrion NV, Maylie J, Adelman JP | title = Small-conductance, calcium-activated potassium channels from mammalian brain | journal = Science (journal) | volume = 273 | issue = 5282 | pages = 1709–14 | year = 1996 | month = September | pmid = 8781233 | doi = 10.1126/science.273.5282.1709 | url = | issn = }}</ref><ref name="pmid15127180"/> and is readily blocked by [[apamin]]. The gene for K<sub>Ca</sub>2.3, KCNN3, is located on [[chromosome]] 1q21.

==Expression==
K<sub>Ca</sub>2.3 is found in almost every tissue in the human body, with exceptions being the [[pancreas]], [[placenta]], [[adipose tissue]], [[liver]], [[prostate]] and [[skin]].<ref name="pmid15127180"/> K<sub>Ca</sub>2.3 is most abundant in regions of the [[brain]], but has also been found to be expressed in significant levels in many other [[peripheral tissue]]s, particularly those rich in [[smooth muscle]], including the [[rectum]], [[corpus cavernosum]], [[Colon (anatomy)|colon]], [[small intestine]] and [[myometirum]].<ref name="pmid15127180"/>

The [[gene expression|expression]] level of KCNN3 is dependent on [[hormone|hormonal]] regulation, particularly by the [[sex hormone]] [[estrogen]]. Estrogen not only enhances [[transcription (genetics)|transcription]] of the KCNN3 gene, but also affects the activity of K<sub>Ca</sub>2.3 channels on the [[cell membrane]]. In [[GABA]]ergic [[POA neurons]], estrogen enhanced the ability of [[alpha-1 adrenergic receptor|α1 adrenergic receptor]]s to inhibit K<sub>Ca</sub>2.3 activity, increasing cell excitability.<ref name="pmid12659870">{{cite journal | author = Jacobson D, Pribnow D, Herson PS, Maylie J, Adelman JP | title = Determinants contributing to estrogen-regulated expression of SK3 | journal = Biochem. Biophys. Res. Commun. | volume = 303 | issue = 2 | pages = 660–8 | year = 2003 | month = April | pmid = 12659870 | doi = 10.1016/S0006-291X(03)00408-X| url = }}</ref> Links between hormonal regulation of [[sex organ]] function and K<sub>Ca</sub>2.3 expression have been established. The expression of K<sub>Ca</sub>2.3 in the corpus cavernosum in patients undergoing estrogen treatment as part of [[gender reassignment surgery]] was found to be increased up to 5-fold.<ref name="pmid15127180"/> The influence of estrogen on K<sub>Ca</sub>2.3 has also been established in the [[hypothalamus]], [[uterus|uterine]] and [[skeletal muscle]].<ref name="pmid12659870"/>

==Physiology==
K<sub>Ca</sub>2.3 channels play a major role in human physiology, particularly in [[smooth muscle]] relaxation. The expression level of K<sub>Ca</sub>2.3 channels in the [[endothelium]] influences [[artery|arterial]] tone by setting arterial smooth muscle [[membrane potential]]. The sustained activity of K<sub>Ca</sub>2.3 channels induces a sustained [[hyperpolarization (biology)|hyperpolarisation]] of the endothelial cell membrane potential, which is then carried to nearby smooth muscle through gap junctions.<ref name="pmid12805243">{{cite journal | author = Taylor MS, Bonev AD, Gross TP, Eckman DM, Brayden JE, Bond CT, Adelman JP, Nelson MT | title = Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure | journal = Circ. Res. | volume = 93 | issue = 2 | pages = 124–31 | year = 2003 | month = July | pmid = 12805243 | doi = 10.1161/01.RES.0000081980.63146.69 | url =  }}</ref> Blocking the K<sub>Ca</sub>2.3 channel or suppressing K<sub>Ca</sub>2.3 expression causes a greatly increased tone in resistance arteries, producing an increase in peripheral resistance and [[blood pressure]].

==Pathology==
[[Mutation]]s in K<sub>Ca</sub>2.3 are suspected to be a possible underlying cause for several [[neurological disorder]]s, including [[schizophrenia]], [[bipolar disorder]], [[Alzheimer’s disease]], [[anorexia nervosa]] and [[ataxia]]<ref name="pmid15389773">{{cite journal | author = 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 | title = 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 | journal = Am. J. Med. Genet. B Neuropsychiatr. Genet. | volume = 131B | issue = 1 | pages = 76–80 | year = 2004 | month = November | pmid = 15389773 | doi = 10.1002/ajmg.b.20154 | url =  }}</ref><ref name="pmid16157352">{{cite journal | author = 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 | title = Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca(2+)-activated K+ channel to genetic predisposition to anorexia nervosa | journal = J Psychiatr Res | volume = 41 | issue = 1-2 | pages = 160–7 | year = 2007 | pmid = 16157352 | doi = 10.1016/j.jpsychires.2005.07.010 | url =  }}</ref><ref name="pmid12808432">{{cite journal | author = Tomita H, Shakkottai VG, Gutman GA, Sun G, Bunney WE, Cahalan MD, Chandy KG, Gargus JJ | title = Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia | journal = Mol. Psychiatry | volume = 8 | issue = 5 | pages = 524–35, 460 | year = 2003 | month = May | pmid = 12808432 | doi = 10.1038/sj.mp.4001271 | url =  }}</ref> as well as [[myotonic muscular dystrophy]].<ref name="pmid12875918">{{cite journal | author = Kimura T, Takahashi MP, Fujimura H, Sakoda S | title = 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 | journal = Neurosci. Lett. | volume = 347 | issue = 3 | pages = 191–5 | year = 2003 | month = August | pmid = 12875918 | doi = 10.1016/S0304-3940(03)00638-4| url = }}</ref>

==References==
{{Reflist}}

==Further reading==
{{refbegin | 2}}
*{{cite journal  |author=Glatt SJ, Faraone SV, Tsuang MT |title=CAG-repeat length in exon 1 of KCNN3 does not influence risk for schizophrenia or bipolar disorder: a meta-analysis of association studies. |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=121B |issue= 1 |pages= 14–20 |year= 2003 |pmid= 12898569 |doi= 10.1002/ajmg.b.20048 }}
*{{cite journal  |author=IvkoviÄ‡ M, RankoviÄ‡ V, Tarasjev A, ''et al.'' |title=Schizophrenia and polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene in Serbian population. |journal=Int. J. Neurosci. |volume=116 |issue= 2 |pages= 157–64 |year= 2006 |pmid= 16393881 |doi= 10.1080/00207450341514 }}
*{{cite journal  |author=Uhl GR, Liu QR, Drgon T, ''et al.'' |title=Molecular genetics of successful smoking cessation: convergent genome-wide association study results. |journal=Arch. Gen. Psychiatry |volume=65 |issue= 6 |pages= 683–93 |year= 2008 |pmid= 18519826 |doi= 10.1001/archpsyc.65.6.683  |pmc=2430596 }}
*{{cite journal  |author=Curtain R, Sundholm J, Lea R, ''et al.'' |title=Association analysis of a highly polymorphic CAG Repeat in the human potassium channel gene KCNN3 and migraine susceptibility. |journal=BMC Med. Genet. |volume=6 |issue=  |pages= 32 |year= 2005 |pmid= 16162291 |doi= 10.1186/1471-2350-6-32  |pmc=1236929 }}
*{{cite journal  |author=Dagle JM, Lepp NT, Cooper ME, ''et al.'' |title=Determination of genetic predisposition to patent ductus arteriosus in preterm infants. |journal=Pediatrics |volume=123 |issue= 4 |pages= 1116–23 |year= 2009 |pmid= 19336370 |doi= 10.1542/peds.2008-0313  |pmc=2734952 }}
*{{cite journal  |author=Rinaldi F, Botta A, Vallo L, ''et al.'' |title=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. |journal=Acta Myol |volume=27 |issue=  |pages= 82–9 |year= 2008 |pmid= 19472917 |doi=  }}
*{{cite journal  |author=Decimo I, Roncarati R, Grasso S, ''et al.'' |title=SK3 trafficking in hippocampal cells: the role of different molecular domains. |journal=Biosci. Rep. |volume=26 |issue= 6 |pages= 399–412 |year= 2006 |pmid= 17061167 |doi= 10.1007/s10540-006-9029-5 }}
*{{cite journal  |author=Laurent C, Niehaus D, BauchÃ© S, ''et al.'' |title=CAG repeat polymorphisms in KCNN3 (HSKCa3) and PPP2R2B show no association or linkage to schizophrenia. |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=116B |issue= 1 |pages= 45–50 |year= 2003 |pmid= 12497613 |doi= 10.1002/ajmg.b.10797 }}
*{{cite journal  |author=Ritsner M, Amir S, Koronyo-Hamaoui M, ''et al.'' |title=Association study of CAG repeats in the KCNN3 gene in Israeli patients with major psychosis. |journal=Psychiatr. Genet. |volume=13 |issue= 3 |pages= 143–50 |year= 2003 |pmid= 12960745 |doi= 10.1097/01.ypg.0000066965.80715.f4 }}
*{{cite journal  |author=Gao Y, Chotoo CK, Balut CM, ''et al.'' |title=Role of S3 and S4 transmembrane domain charged amino acids in channel biogenesis and gating of KCa2.3 and KCa3.1. |journal=J. Biol. Chem. |volume=283 |issue= 14 |pages= 9049–59 |year= 2008 |pmid= 18227067 |doi= 10.1074/jbc.M708022200  |pmc=2431042 }}
*{{cite journal  |author=Zhou Z, Jiang DJ, Jia SJ, ''et al.'' |title=Down-regulation of endogenous nitric oxide synthase inhibitors on endothelial SK3 expression. |journal=Vascul. Pharmacol. |volume=47 |issue= 5-6 |pages= 265–71 |year=  2007|pmid= 17869187 |doi= 10.1016/j.vph.2007.08.003 }}
*{{cite journal  |author=Koronyo-Hamaoui M, Gak E, Stein D, ''et al.'' |title=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. |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=131B |issue= 1 |pages= 76–80 |year= 2004 |pmid= 15389773 |doi= 10.1002/ajmg.b.20154 }}
*{{cite journal  |author=Kolski-Andreaco A, Tomita H, Shakkottai VG, ''et al.'' |title=SK3-1C, a dominant-negative suppressor of SKCa and IKCa channels. |journal=J. Biol. Chem. |volume=279 |issue= 8 |pages= 6893–904 |year= 2004 |pmid= 14638680 |doi= 10.1074/jbc.M311725200 }}
*{{cite journal  |author=Wei AD, Gutman GA, Aldrich R, ''et al.'' |title=International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels. |journal=Pharmacol. Rev. |volume=57 |issue= 4 |pages= 463–72 |year= 2005 |pmid= 16382103 |doi= 10.1124/pr.57.4.9 }}
*{{cite journal  |author=Piotrowska AP, Solari V, Puri P |title=Distribution of Ca2+-activated K channels, SK2 and SK3, in the normal and Hirschsprung's disease bowel. |journal=J. Pediatr. Surg. |volume=38 |issue= 6 |pages= 978–83 |year= 2003 |pmid= 12778407 |doi=10.1016/S0022-3468(03)00138-6  }}
*{{cite journal  |author=Hong XH, Xu CT, Yang Q, Wu CR |title=[Transmission disequilibrium analysis of 1137-1140 Del GTGA frameshift mutation within the KCNN3 gene and schizophrenia based on family trios] |journal=Zhonghua Yi Xue Yi Chuan Xue Za Zhi |volume=22 |issue= 4 |pages= 441–3 |year= 2005 |pmid= 16086287 |doi=  }}
*{{cite journal  |author=Rhodes JD, Monckton DG, McAbney JP, ''et al.'' |title=Increased SK3 expression in DM1 lens cells leads to impaired growth through a greater calcium-induced fragility. |journal=Hum. Mol. Genet. |volume=15 |issue= 24 |pages= 3559–68 |year= 2006 |pmid= 17101631 |doi= 10.1093/hmg/ddl432 }}
*{{cite journal  |author=Tomita H, Shakkottai VG, Gutman GA, ''et al.'' |title=Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia. |journal=Mol. Psychiatry |volume=8 |issue= 5 |pages= 524–35, 460 |year= 2003 |pmid= 12808432 |doi= 10.1038/sj.mp.4001271 }}
*{{cite journal  |author=Monaghan AS, Benton DC, Bahia PK, ''et al.'' |title=The SK3 subunit of small conductance Ca2+-activated K+ channels interacts with both SK1 and SK2 subunits in a heterologous expression system. |journal=J. Biol. Chem. |volume=279 |issue= 2 |pages= 1003–9 |year= 2004 |pmid= 14559917 |doi= 10.1074/jbc.M308070200 }}
*{{cite journal  |author=de Krom M, Staal WG, Ophoff RA, ''et al.'' |title=A common variant in DRD3 receptor is associated with autism spectrum disorder. |journal=Biol. Psychiatry |volume=65 |issue= 7 |pages= 625–30 |year= 2009 |pmid= 19058789 |doi= 10.1016/j.biopsych.2008.09.035 }}
{{refend}}

{{Ion channels|g3}}

[[Category:Neurochemistry]]
[[Category:Ion channels]]
[[Category:2Fix]]