Biology:SK3
 Generic protein structure example |
SK3 (small conductance calcium-activated potassium channel 3) also known as KCa2.3 is a protein that in humans is encoded by the KCNN3 gene.[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.
Structure
KCa2.3 contains 6 transmembrane domains, a pore-forming region, and intracellular N- and C- termini[3][4] and is readily blocked by apamin. The gene for KCa2.3, KCNN3, is located on chromosome 1q21.
Expression
KCa2.3 is found in the central nervous system (CNS), muscle, liver, pituitary, prostate, kidney, pancreas and vascular endothelium tissues.[5] 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 myometrium.[3]
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 preoptic 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.
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[8][9][10] as well as myotonic muscular dystrophy.[11]
References
- ↑ "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. January 1998. doi:10.1038/sj.mp.4000353. PMID 9491810.
- ↑ 2.0 2.1 "International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels". Pharmacol. Rev. 57 (4): 463–72. December 2005. doi:10.1124/pr.57.4.9. PMID 16382103. https://semanticscholar.org/paper/a97177eb871fe0ab90795bb81c721fcff82ca28d.
- ↑ 3.0 3.1 3.2 3.3 "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. June 2004. doi:10.1007/s00210-004-0934-5. PMID 15127180.
- ↑ "Small-conductance, calcium-activated potassium channels from mammalian brain". Science 273 (5282): 1709–14. September 1996. doi:10.1126/science.273.5282.1709. PMID 8781233. Bibcode: 1996Sci...273.1709K.
- ↑ "Modulators of small- and intermediate-conductance calcium-activated potassium channels and their therapeutic indications". Curr. Med. Chem. 14 (13): 1437–57. 2007. doi:10.2174/092986707780831186. PMID 17584055.
- ↑ 6.0 6.1 "Determinants contributing to estrogen-regulated expression of SK3". Biochem. Biophys. Res. Commun. 303 (2): 660–8. April 2003. doi:10.1016/S0006-291X(03)00408-X. PMID 12659870.
- ↑ "Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure". Circ. Res. 93 (2): 124–31. July 2003. doi:10.1161/01.RES.0000081980.63146.69. PMID 12805243.
- ↑ "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. November 2004. doi:10.1002/ajmg.b.20154. PMID 15389773.
- ↑ "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. 2007. doi:10.1016/j.jpsychires.2005.07.010. PMID 16157352.
- ↑ "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. May 2003. doi:10.1038/sj.mp.4001271. PMID 12808432.
- ↑ "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. August 2003. doi:10.1016/S0304-3940(03)00638-4. PMID 12875918.
Further reading
- "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. 2003. doi:10.1002/ajmg.b.20048. PMID 12898569.
- "Schizophrenia and polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene in Serbian population.". Int. J. Neurosci. 116 (2): 157–64. 2006. doi:10.1080/00207450341514. PMID 16393881.
- "Molecular genetics of successful smoking cessation: convergent genome-wide association study results.". Arch. Gen. Psychiatry 65 (6): 683–93. 2008. doi:10.1001/archpsyc.65.6.683. PMID 18519826.
- "Association analysis of a highly polymorphic CAG Repeat in the human potassium channel gene KCNN3 and migraine susceptibility.". BMC Med. Genet. 6: 32. 2005. doi:10.1186/1471-2350-6-32. PMID 16162291.
- "Determination of genetic predisposition to patent ductus arteriosus in preterm infants.". Pediatrics 123 (4): 1116–23. 2009. doi:10.1542/peds.2008-0313. PMID 19336370.
- "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. 2008. PMID 19472917.
- "SK3 trafficking in hippocampal cells: the role of different molecular domains.". Biosci. Rep. 26 (6): 399–412. 2006. doi:10.1007/s10540-006-9029-5. PMID 17061167.
- "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. 2003. doi:10.1002/ajmg.b.10797. PMID 12497613.
- "Association study of CAG repeats in the KCNN3 gene in Israeli patients with major psychosis.". Psychiatr. Genet. 13 (3): 143–50. 2003. doi:10.1097/00041444-200309000-00002. PMID 12960745.
- "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. 2008. doi:10.1074/jbc.M708022200. PMID 18227067.
- "Down-regulation of endogenous nitric oxide synthase inhibitors on endothelial SK3 expression.". Vascul. Pharmacol. 47 (5–6): 265–71. 2007. doi:10.1016/j.vph.2007.08.003. PMID 17869187.
- "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. 2004. doi:10.1002/ajmg.b.20154. PMID 15389773.
- "SK3-1C, a dominant-negative suppressor of SKCa and IKCa channels.". J. Biol. Chem. 279 (8): 6893–904. 2004. doi:10.1074/jbc.M311725200. PMID 14638680.
- "Distribution of Ca2+-activated K channels, SK2 and SK3, in the normal and Hirschsprung's disease bowel.". J. Pediatr. Surg. 38 (6): 978–83. 2003. doi:10.1016/S0022-3468(03)00138-6. PMID 12778407.
- "[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. 2005. PMID 16086287.
- "Increased SK3 expression in DM1 lens cells leads to impaired growth through a greater calcium-induced fragility.". Hum. Mol. Genet. 15 (24): 3559–68. 2006. doi:10.1093/hmg/ddl432. PMID 17101631.
- "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. 2003. doi:10.1038/sj.mp.4001271. PMID 12808432.
- "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. 2004. doi:10.1074/jbc.M308070200. PMID 14559917.
- "A common variant in DRD3 receptor is associated with autism spectrum disorder.". Biol. Psychiatry 65 (7): 625–30. 2009. doi:10.1016/j.biopsych.2008.09.035. PMID 19058789.
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