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KCNN3
Identifiers
Aliases	KCNN3, KCa2.3, SK3, SKCA3, hSK3, potassium calcium-activated channel subfamily N member 3, ZLS3
External IDs	OMIM: 602983; MGI: 2153183; HomoloGene: 20516; GeneCards: KCNN3; OMA:KCNN3 - orthologs
Gene location (Human)
Chr.	Chromosome 1 (human)
End	154,870,281 bp
Gene location (Mouse)
Chr.	Chromosome 3 (mouse)
End	89,582,439 bp
RNA expression pattern
	Top expressed in
	external globus pallidus; ; pars reticulata; ; internal globus pallidus; ; pars compacta; ; dorsal motor nucleus of vagus nerve; ; ventral tegmental area; ; superior vestibular nucleus; ; entorhinal cortex; ; tendon of biceps brachii; ; lateral nuclear group of thalamus;
	Top expressed in
	dentate gyrus of hippocampal formation granule cell; ; superior frontal gyrus; ; ascending aorta; ; primary visual cortex; ; aortic valve; ; ventricular zone; ; ganglionic eminence; ; embryo; ; supraoptic nucleus; ; esophagus;
	More reference expression data
	n/a
Gene ontology
Molecular function	small conductance calcium-activated potassium channel activity; calcium-activated potassium channel activity; calmodulin binding;
Cellular component	integral component of membrane; soma; plasma membrane; membrane; neuron projection;
Biological process	potassium ion transport; ion transport; potassium ion transmembrane transport;
	Sources:Amigo / QuickGO
Orthologs
	3782
	140493
	ENSG00000143603
	ENSMUSG00000000794
	Q9UGI6
	P58391
	NM_170782; NM_001204087; NM_002249; NM_001365837; NM_001365838
	NM_080466
	NP_001191016; NP_002240; NP_740752; NP_001352766; NP_001352767
	NP_536714
	Wikidata
View/Edit Human	View/Edit Mouse

SK3 (small conductance calcium-activated potassium channel 3) also known as K_Ca2.3 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 (I_AHP). 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, K_Ca2.1 (SK1), K_Ca2.2 (SK2) and K_Ca2.3 (SK3).^[6] Small conductance channels are responsible for the medium and possibly the slow components of the I_AHP.

Structure

K_Ca2.3 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 K_Ca2.3, KCNN3, is located on chromosome 1q21.

Expression

K_Ca2.3 is found in the central nervous system (CNS), muscle, liver, pituitary, prostate, kidney, pancreas and vascular endothelium tissues.^[9] K_Ca2.3 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 K_Ca2.3 channels on the cell membrane. In GABAergic preoptic area neurons, estrogen enhanced the ability of α1 adrenergic receptors to inhibit K_Ca2.3 activity, increasing cell excitability.^[10] Links between hormonal regulation of sex organ function and K_Ca2.3 expression have been established. The expression of K_Ca2.3 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 K_Ca2.3 has also been established in the hypothalamus, uterine and skeletal muscle.^[10]

Physiology

K_Ca2.3 channels play a major role in human physiology, particularly in smooth muscle relaxation. The expression level of K_Ca2.3 channels in the endothelium influences arterial tone by setting arterial smooth muscle membrane potential. The sustained activity of K_Ca2.3 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 K_Ca2.3 channel or suppressing K_Ca2.3 expression causes a greatly increased tone in resistance arteries, producing an increase in peripheral resistance and blood pressure.

Pathology

Mutations in K_Ca2.3 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

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000143603 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000000794 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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.
^ ^a ^b 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.
^ ^a ^b ^c ^d 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-Schmiedeberg's Arch. Pharmacol. 369 (6): 602–15. doi:10.1007/s00210-004-0934-5. PMID 15127180. S2CID 6309146.
^ 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.
^ 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.
^ ^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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.

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. S2CID 7397950.
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. S2CID 31789520.
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. 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. 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. 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 (3): 82–9. PMC 2858941. 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. S2CID 38653604.
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. S2CID 20643826.
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:10.1097/00041444-200309000-00002. PMID 12960745. S2CID 11378997.
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. 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. S2CID 24415070.
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.
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. S2CID 1569495.
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. S2CID 11545813.