SK3
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| potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3 | |||||||||||||
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| Identifiers | |||||||||||||
| Symbols | KCNN3; SKCA3; hSK3; SK3 | ||||||||||||
| External IDs | OMIM: 602983 MGI: 2153183 HomoloGene: 20516 IUPHAR: KCa2.3 GeneCards: KCNN3 Gene | ||||||||||||
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| 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.
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
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- 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. PMC 2430596 Freely accessible. 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. PMC 1236929 Freely accessible. 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. PMC 2734952 Freely accessible. 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. PMC 2431042 Freely accessible. PMID 18227067.
- 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. 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. doi:10.1016/S0022-3468(03)00138-6. 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.
- ↑ 1.0 1.1 1.2 1.3 1.4 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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- ↑ 4.0 4.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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- ↑ 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.
- ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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