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Target id: 382
Nomenclature: KCa2.2
Family: Calcium- and sodium-activated potassium channels (KCa, KNa)
Gene and Protein Information | |||||||
Species | TM | P Loops | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 6 | 1 | 579 | 5q22.3 | KCNN2 | potassium calcium-activated channel subfamily N member 2 | 14,22,32 |
Mouse | 6 | 1 | 839 | 18 B3-C | Kcnn2 | potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2 | 7,47,55 |
Rat | 6 | 1 | 580 | 18q11 | Kcnn2 | potassium calcium-activated channel subfamily N member 2 | 34,55 |
Database Links | |
Alphafold | Q9H2S1 (Hs), P58390 (Mm), P70604 (Rn) |
ChEMBL Target | CHEMBL4469 (Hs), CHEMBL2547 (Rn) |
Ensembl Gene | ENSG00000080709 (Hs), ENSMUSG00000054477 (Mm), ENSRNOG00000016675 (Rn) |
Entrez Gene | 3781 (Hs), 140492 (Mm), 54262 (Rn) |
Human Protein Atlas | ENSG00000080709 (Hs) |
KEGG Gene | hsa:3781 (Hs), mmu:140492 (Mm), rno:54262 (Rn) |
OMIM | 605879 (Hs) |
Pharos | Q9H2S1 (Hs) |
RefSeq Nucleotide | NM_021614 (Hs), NM_170775 (Hs), NM_080465 (Mm), NM_019314 (Rn) |
RefSeq Protein | NP_740721 (Hs), NP_067627 (Hs), NP_536713 (Mm), NP_062187 (Rn) |
UniProtKB | Q9H2S1 (Hs), P58390 (Mm), P70604 (Rn) |
Wikipedia | KCNN2 (Hs) |
Associated Proteins | ||||||||||||||||||||
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Associated Protein Comments | ||||||||||||||||||||
Casein kinase 2 (CK2) and protein phosphatase 2A (PPA) phosphorylate and dephosphorylate Thr80 in calmodulin changing KCa2.2 Ca2+ sensitivity [1,5]. |
Functional Characteristics | |
SKCa |
Ion Selectivity and Conductance | ||||||
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Voltage Dependence Comments |
KCa2.2 is voltage independent. |
Download all structure-activity data for this target as a CSV file
Activators | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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NS309, riluzole, DC-EBIO and EBIO increase Ca2+ sensitivity of KCa2.2 [44-45]. A detailed review of KCa2 channel pharmacology can be found in [66]. For shorter more recent reviews see [11,67]. |
Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Gating inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Gating Inhibitor Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NS5893 is an inhibitory gating modulator that decreases the Ca2+ sensitivity of KCa2 channels [60]. |
Channel Blockers | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Tamapin, apamin and leiurotoxin I block KCa2.2 at picomolar concentrations and KCa2.1 and KCa2.3 at low nanomolar concentrations. A detailed review of KCa2 channel pharmacology can be found in [66]. For shorter more recent reviews see [11,67]. |
Tissue Distribution | ||||||||
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Physiological Consequences of Altering Gene Expression | ||||||||||
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Phenotypes, Alleles and Disease Models | Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Biologically Significant Variants | ||||||||||||
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General Comments |
Reviews of KCa2.2 channel physiology and pharmacology can be found in [1,55-56,66]. |
1. Adelman JP, Maylie J, Sah P. (2012) Small-conductance Ca2+-activated K+ channels: form and function. Annu Rev Physiol, 74: 245-69. [PMID:21942705]
2. Allen D, Nakayama S, Kuroiwa M, Nakano T, Palmateer J, Kosaka Y, Ballesteros C, Watanabe M, Bond CT, Luján R et al.. (2011) SK2 channels are neuroprotective for ischemia-induced neuronal cell death. J Cereb Blood Flow Metab, 31 (12): 2302-12. [PMID:21712833]
3. Alviña K, Khodakhah K. (2010) KCa channels as therapeutic targets in episodic ataxia type-2. J Neurosci, 30 (21): 7249-57. [PMID:20505091]
4. Anderson NJ, Slough S, Watson WP. (2006) In vivo characterisation of the small-conductance KCa (SK) channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) as a potential anticonvulsant. Eur J Pharmacol, 546 (1-3): 48-53. [PMID:16925994]
5. Bildl W, Strassmaier T, Thurm H, Andersen J, Eble S, Oliver D, Knipper M, Mann M, Schulte U, Adelman JP et al.. (2004) Protein kinase CK2 is coassembled with small conductance Ca(2+)-activated K+ channels and regulates channel gating. Neuron, 43 (6): 847-58. [PMID:15363395]
6. Blank T, Nijholt I, Kye MJ, Spiess J. (2004) Small conductance Ca2+-activated K+ channels as targets of CNS drug development. Curr Drug Targets CNS Neurol Disord, 3 (3): 161-7. [PMID:15180477]
7. Bond CT, Herson PS, Strassmaier T, Hammond R, Stackman R, Maylie J, Adelman JP. (2004) Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents. J Neurosci, 24 (23): 5301-6. [PMID:15190101]
8. Cao Y, Dreixler JC, Roizen JD, Roberts MT, Houamed KM. (2001) Modulation of recombinant small-conductance Ca(2+)-activated K(+) channels by the muscle relaxant chlorzoxazone and structurally related compounds. J Pharmacol Exp Ther, 296 (3): 683-9. [PMID:11181893]
9. Cao YJ, Dreixler JC, Couey JJ, Houamed KM. (2002) Modulation of recombinant and native neuronal SK channels by the neuroprotective drug riluzole. Eur J Pharmacol, 449 (1-2): 47-54. [PMID:12163105]
10. Chen MX, Gorman SA, Benson B, Singh K, Hieble JP, Michel MC, Tate SN, Trezise DJ. (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. [PMID:15127180]
11. Christophersen P, Wulff H. (2015) Pharmacological gating modulation of small- and intermediate-conductance Ca(2+)-activated K(+) channels (KCa2.x and KCa3.1). Channels (Austin), 9 (6): 336-43. [PMID:26217968]
12. Cingolani LA, Gymnopoulos M, Boccaccio A, Stocker M, Pedarzani P. (2002) Developmental regulation of small-conductance Ca2+-activated K+ channel expression and function in rat Purkinje neurons. J Neurosci, 22 (11): 4456-67. [PMID:12040053]
13. Coleman N, Nguyen HM, Cao Z, Brown BM, Jenkins DP, Zolkowska D, Chen YJ, Tanaka BS, Goldin AL, Rogawski MA et al.. (2015) The riluzole derivative 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a mixed KCa2 activator and NaV blocker, is a potent novel anticonvulsant. Neurotherapeutics, 12 (1): 234-49. [PMID:25256961]
14. Desai R, Peretz A, Idelson H, Lazarovici P, Attali B. (2000) Ca2+-activated K+ channels in human leukemic Jurkat T cells. Molecular cloning, biochemical and functional characterization. J Biol Chem, 275 (51): 39954-63. [PMID:10991935]
15. Deschaux O, Bizot JC. (2005) Apamin produces selective improvements of learning in rats. Neurosci Lett, 386 (1): 5-8. [PMID:15985330]
16. Deschaux O, Bizot JC, Goyffon M. (1997) Apamin improves learning in an object recognition task in rats. Neurosci Lett, 222 (3): 159-62. [PMID:9148239]
17. Diness JG, Skibsbye L, Jespersen T, Bartels ED, Sørensen US, Hansen RS, Grunnet M. (2011) Effects on atrial fibrillation in aged hypertensive rats by Ca(2+)-activated K(+) channel inhibition. Hypertension, 57 (6): 1129-35. [PMID:21502564]
18. Dolga AM, Terpolilli N, Kepura F, Nijholt IM, Knaus HG, D'Orsi B, Prehn JH, Eisel UL, Plant T, Plesnila N et al.. (2011) KCa2 channels activation prevents [Ca2+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia. Cell Death Dis, 2: e147. [PMID:21509037]
19. Dreixler JC, Bian J, Cao Y, Roberts MT, Roizen JD, Houamed KM. (2000) Block of rat brain recombinant SK channels by tricyclic antidepressants and related compounds. Eur J Pharmacol, 401 (1): 1-7. [PMID:10915830]
20. Fanger CM, Rauer H, Neben AL, Miller MJ, Rauer H, Wulff H, Rosa JC, Ganellin CR, Chandy KG, Cahalan MD. (2001) Calcium-activated potassium channels sustain calcium signaling in T lymphocytes. Selective blockers and manipulated channel expression levels. J Biol Chem, 276 (15): 12249-56. [PMID:11278890]
21. Feranchak AP, Doctor RB, Troetsch M, Brookman K, Johnson SM, Fitz JG. (2004) Calcium-dependent regulation of secretion in biliary epithelial cells: the role of apamin-sensitive SK channels. Gastroenterology, 127 (3): 903-13. [PMID:15362045]
22. Ghanshani S, Wulff H, Miller MJ, Rohm H, Neben A, Gutman GA, Cahalan MD, Chandy KG. (2000) Up-regulation of the IKCa1 potassium channel during T-cell activation. Molecular mechanism and functional consequences. J Biol Chem, 275 (47): 37137-49. [PMID:10961988]
23. Grissmer S, Lewis RS, Cahalan MD. (1992) Ca(2+)-activated K+ channels in human leukemic T cells. J Gen Physiol, 99 (1): 63-84. [PMID:1371308]
24. Hammond RS, Bond CT, Strassmaier T, Ngo-Anh TJ, Adelman JP, Maylie J, Stackman RW. (2006) Small-conductance Ca2+-activated K+ channel type 2 (SK2) modulates hippocampal learning, memory, and synaptic plasticity. J Neurosci, 26 (6): 1844-53. [PMID:16467533]
25. Haugaard MM, Hesselkilde EZ, Pehrson S, Carstensen H, Flethøj M, Præstegaard KF, Sørensen US, Diness JG, Grunnet M, Buhl R et al.. (2015) Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses. Heart Rhythm, 12 (4): 825-35. [PMID:25542425]
26. Hirschberg B, Maylie J, Adelman JP, Marrion NV. (1998) Gating of recombinant small-conductance Ca-activated K+ channels by calcium. J Gen Physiol, 111 (4): 565-81. [PMID:9524139]
27. Hopf FW, Bowers MS, Chang SJ, Chen BT, Martin M, Seif T, Cho SL, Tye K, Bonci A. (2010) Reduced nucleus accumbens SK channel activity enhances alcohol seeking during abstinence. Neuron, 65 (5): 682-94. [PMID:20223203]
28. Hopf FW, Seif T, Bonci A. (2011) The SK channel as a novel target for treating alcohol use disorders. Channels (Austin), 5 (4): 289-92. [PMID:21712648]
29. Hopf FW, Simms JA, Chang SJ, Seif T, Bartlett SE, Bonci A. (2011) Chlorzoxazone, an SK-type potassium channel activator used in humans, reduces excessive alcohol intake in rats. Biol Psychiatry, 69 (7): 618-24. [PMID:21195386]
30. Hougaard C, Eriksen BL, Jørgensen S, Johansen TH, Dyhring T, Madsen LS, Strøbaek D, Christophersen P. (2007) Selective positive modulation of the SK3 and SK2 subtypes of small conductance Ca2+-activated K+ channels. Br J Pharmacol, 151 (5): 655-65. [PMID:17486140]
31. Ishii TM, Maylie J, Adelman JP. (1997) Determinants of apamin and d-tubocurarine block in SK potassium channels. J Biol Chem, 272 (37): 23195-200. [PMID:9287325]
32. Jäger H, Adelman JP, Grissmer S. (2000) SK2 encodes the apamin-sensitive Ca(2+)-activated K(+) channels in the human leukemic T cell line, Jurkat. FEBS Lett, 469 (2-3): 196-202. [PMID:10713270]
33. Kasumu AW, Hougaard C, Rode F, Jacobsen TA, Sabatier JM, Eriksen BL, Strøbæk D, Liang X, Egorova P, Vorontsova D et al.. (2012) Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2. Chem Biol, 19 (10): 1340-53. [PMID:23102227]
34. Kohler M, Hirschberg B, Bond CT, Kinzie JM, Marrion NV, Maylie J, Adelman JP. (1996) Small-conductance, calcium-activated potassium channels from mammalian brain. Science, 273 (5282): 1709-14. [PMID:8781233]
35. Lam J, Coleman N, Garing AL, Wulff H. (2013) The therapeutic potential of small-conductance KCa2 channels in neurodegenerative and psychiatric diseases. Expert Opin Ther Targets, 17 (10): 1203-20. [PMID:23883298]
36. Lappin SC, Dale TJ, Brown JT, Trezise DJ, Davies CH. (2005) Activation of SK channels inhibits epileptiform bursting in hippocampal CA3 neurons. Brain Res, 1065 (1-2): 37-46. [PMID:16336949]
37. Messier C, Mourre C, Bontempi B, Sif J, Lazdunski M, Destrade C. (1991) Effect of apamin, a toxin that inhibits Ca(2+)-dependent K+ channels, on learning and memory processes. Brain Res, 551 (1-2): 322-6. [PMID:1913161]
38. Monaghan AS, Benton DC, Bahia PK, Hosseini R, Shah YA, Haylett DG, Moss GW. (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. [PMID:14559917]
39. Mourre C, Fournier C, Soumireu-Mourat B. (1997) Apamin, a blocker of the calcium-activated potassium channel, induces neurodegeneration of Purkinje cells exclusively. Brain Res, 778 (2): 405-8. [PMID:9459560]
40. Mulholland PJ, Becker HC, Woodward JJ, Chandler LJ. (2011) Small conductance calcium-activated potassium type 2 channels regulate alcohol-associated plasticity of glutamatergic synapses. Biol Psychiatry, 69 (7): 625-32. [PMID:21056409]
41. Oliván-Viguera A, Valero MS, Coleman N, Brown BM, Laría C, Murillo MD, Gálvez JA, Díaz-de-Villegas MD, Wulff H, Badorrey R et al.. (2015) A novel pan-negative-gating modulator of KCa2/3 channels, fluoro-di-benzoate, RA-2, inhibits endothelium-derived hyperpolarization-type relaxation in coronary artery and produces bradycardia in vivo. Mol Pharmacol, 87 (2): 338-48. [PMID:25468883]
42. Orfila JE, Shimizu K, Garske AK, Deng G, Maylie J, Traystman RJ, Quillinan N, Adelman JP, Herson PS. (2014) Increasing small conductance Ca2+-activated potassium channel activity reverses ischemia-induced impairment of long-term potentiation. Eur J Neurosci, 40 (8): 3179-88. [PMID:25080203]
43. Pedarzani P, D'hoedt D, Doorty KB, Wadsworth JD, Joseph JS, Jeyaseelan K, Kini RM, Gadre SV, Sapatnekar SM, Stocker M et al.. (2002) Tamapin, a venom peptide from the Indian red scorpion (Mesobuthus tamulus) that targets small conductance Ca2+-activated K+ channels and afterhyperpolarization currents in central neurons. J Biol Chem, 277 (48): 46101-9. [PMID:12239213]
44. Pedarzani P, McCutcheon JE, Rogge G, Jensen BS, Christophersen P, Hougaard C, Strøbaek D, Stocker M. (2005) Specific enhancement of SK channel activity selectively potentiates the afterhyperpolarizing current I(AHP) and modulates the firing properties of hippocampal pyramidal neurons. J Biol Chem, 280 (50): 41404-11. [PMID:16239218]
45. Pedarzani P, Mosbacher J, Rivard A, Cingolani LA, Oliver D, Stocker M, Adelman JP, Fakler B. (2001) Control of electrical activity in central neurons by modulating the gating of small conductance Ca2+-activated K+ channels. J Biol Chem, 276 (13): 9762-9. [PMID:11134030]
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