Target has curated data in GtoImmuPdb
Contents:
- Gene and Protein Information
- Previous and Unofficial Names
- Database Links
- Associated Proteins
- Functional Characteristics
- Ion Selectivity and Conductance
- Voltage Dependence
- Activators
- Gating Inhibitors
- Channel Blockers
- Immunopharmacology Comments
- Immuno Cell Type Associations
- Immuno Process Associations
- Tissue Distribution
- Functional Assays
- Physiological Functions
- Phenotypes, Alleles and Disease Models
- Clinically-Relevant Mutations and Pathophysiology
- Gene Expression and Pathophysiology
- References
- Contributors
- How to cite this page
Gene and Protein Information  |
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| Species | TM | P Loops | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 6 | 1 | 427 | 19q13.31 | KCNN4 | potassium calcium-activated channel subfamily N member 4 | 22-23,27,29,39 |
| Mouse | 6 | 1 | 425 | 7 A3 | Kcnn4 | potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4 | 67 |
| Rat | 6 | 1 | 425 | 1q21 | Kcnn4 | potassium calcium-activated channel subfamily N member 4 | 69 |
| Previous and Unofficial Names |
| Gardos channel | IKCa1 | Ik1 | KCa4 | intermediate-conductance Ca-activated K channel | SK4 | potassium channel, calcium activated intermediate/small conductance subfamily N alpha, member 4 | potassium intermediate/small conductance calcium-activated channel |
| Database Links |
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| ChEMBL Target | CHEMBL4305 (Hs) |
| DrugBank Target | O15554 (Hs) |
| Ensembl Gene | ENSG00000104783 (Hs), ENSMUSG00000054342 (Mm), ENSRNOG00000019440 (Rn) |
| Entrez Gene | 3783 (Hs), 16534 (Mm), 65206 (Rn) |
| Human Protein Atlas | ENSG00000104783 (Hs) |
| KEGG Gene | hsa:3783 (Hs), mmu:16534 (Mm), rno:65206 (Rn) |
| OMIM | 602754 (Hs) |
| Pharos | O15554 (Hs) |
| RefSeq Nucleotide | NM_002250 (Hs), NM_008433 (Mm), NM_023021 (Rn) |
| RefSeq Protein | NP_002241 (Hs), NP_032459 (Mm), NP_075410 (Rn) |
| UniProtKB | O15554 (Hs), O89109 (Mm), Q9QYW1 (Rn) |
| Wikipedia | KCNN4 (Hs) |
| Associated Proteins |
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| Functional Characteristics |
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| IKCa | |
| Ion Selectivity and Conductance |
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| Voltage Dependence Comments |
| KCa3.1 is voltage independent. |
Download all structure-activity data for this target as a CSV file 
| Activators | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Activator Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No species differences described; NS309, DCEBIO, riluzole and EBIO increase the Ca2+ sensitivity of both KCa3.1 and KCa2 channels; see [73-74] for a recent extensive review of KCa3.1 and KCa2 channel pharmacology. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gating Inhibitor Comments | ||
| [1,3-phenylenebis(methylene) bis(3-fluoro-4-hydroxybenzoate) (RA-2) is a negative gating modulator that inhibits KCa3.1 with an IC50 of 17 nM and all three KCa2 channels with similar potency. It right-shifts the Ca2+ activation curve [43]. The inhibitory gating modulator of KCa2 channels NS8593 does not block KCa3.1 [60]. |
| Channel Blockers | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Channel Blocker Comments | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Many more blockers have been characterised; see [73-74] for an extensive review of the pharmacology. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Immunopharmacology Comments |
| KCa3.1 and KV1.3 are the predominant potassium channels involved in regulating the hyperpolarized (negative) membrane potential which is critical for immune cell activation [12,18,40]. KCa3.1 is voltage-independent and is activated by Ca2+ binding to the calmodulin that is always present at the channel's C terminus. In activated T cells, KCa3.1 and KV1.3 localise to the immunological synapse, where interactions with regulatory kinases occurs. In addition to functions in cell cycle progression and cellular proliferation, KCa3.1 channels play an important immunoregulatory role, including participation in pathologic mechanisms that are associated with the inflammatory and proliferative cascades that characterise autoimmune diseases such as rheumatoid arthritis [20,50]. Notably KCa3.1 knockout mice are resistant to experimental collagen‐induced (i.e. autoimmune) arthritis [50]. KCa3.1 is involved in lymphocyte activation, and in the proliferation and migration of T cells, B cells, mast cells, macrophages and fibroblasts. As an inflammation-relevant drug target [71], KCa3.1 modulators are being investigated for potential in the treatment of asthma and fibroproliferative disorders, and for immunosuppressant efficacy [68]. |
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References
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3. Ayabe T, Wulff H, Darmoul D, Cahalan MD, Chandy KG, Ouellette AJ. (2002) Modulation of mouse Paneth cell alpha-defensin secretion by mIKCa1, a Ca2+-activated, intermediate conductance potassium channel. J. Biol. Chem., 277 (5): 3793-800. [PMID:11724775]
4. Begenisich T, Nakamoto T, Ovitt CE, Nehrke K, Brugnara C, Alper SL, Melvin JE. (2004) Physiological roles of the intermediate conductance, Ca2+-activated potassium channel Kcnn4. J. Biol. Chem., 279 (46): 47681-7. [PMID:15347667]
5. Brugnara C, de Franceschi L, Alper SL. (1993) Inhibition of Ca(2+)-dependent K+ transport and cell dehydration in sickle erythrocytes by clotrimazole and other imidazole derivatives. J. Clin. Invest., 92 (1): 520-6. [PMID:8326017]
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20. Friebel K, Schönherr R, Kinne RW, Kunisch E. (2015) Functional role of the KCa3.1 potassium channel in synovial fibroblasts from rheumatoid arthritis patients. J. Cell. Physiol., 230 (7): 1677-88. [PMID:25545021]
21. GARDOS G. (1958) The function of calcium in the potassium permeability of human erythrocytes. Biochim. Biophys. Acta, 30 (3): 653-4. [PMID:13618284]
22. Ghanshani S, Coleman M, Gustavsson P, Wu AC, Gargus JJ, Gutman GA, Dahl N, Mohrenweiser H, Chandy KG. (1998) Human calcium-activated potassium channel gene KCNN4 maps to chromosome 19q13.2 in the region deleted in diamond-blackfan anemia. Genomics, 51 (1): 160-1. [PMID:9693050]
23. 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]
24. Glogowska E, Lezon-Geyda K, Maksimova Y, Schulz VP, Gallagher PG. (2015) Mutations in the Gardos channel (KCNN4) are associated with hereditary xerocytosis. Blood, 126 (11): 1281-4. [PMID:26198474]
25. Grgic I, Eichler I, Heinau P, Si H, Brakemeier S, Hoyer J, Köhler R. (2005) Selective blockade of the intermediate-conductance Ca2+-activated K+ channel suppresses proliferation of microvascular and macrovascular endothelial cells and angiogenesis in vivo. Arterioscler. Thromb. Vasc. Biol., 25 (4): 704-9. [PMID:15662023]
26. Grissmer S, Nguyen AN, Cahalan MD. (1993) Calcium-activated potassium channels in resting and activated human T lymphocytes. Expression levels, calcium dependence, ion selectivity, and pharmacology. J. Gen. Physiol., 102 (4): 601-30. [PMID:7505804]
27. Ishii TM, Silvia C, Hirschberg B, Bond CT, Adelman JP, Maylie J. (1997) A human intermediate conductance calcium-activated potassium channel. Proc. Natl. Acad. Sci. U.S.A., 94 (21): 11651-6. [PMID:9326665]
28. Jensen BS, Strobaek D, Christophersen P, Jorgensen TD, Hansen C, Silahtaroglu A, Olesen SP, Ahring PK. (1998) Characterization of the cloned human intermediate-conductance Ca2+-activated K+ channel. Am. J. Physiol., 275 (3): C848-56. [PMID:9730970]
29. Joiner WJ, Wang LY, Tang MD, Kaczmarek LK. (1997) hSK4, a member of a novel subfamily of calcium-activated potassium channels. Proc. Natl. Acad. Sci. U.S.A., 94 (20): 11013-8. [PMID:9380751]
30. Jäger H, Dreker T, Buck A, Giehl K, Gress T, Grissmer S. (2004) Blockage of intermediate-conductance Ca2+-activated K+ channels inhibit human pancreatic cancer cell growth in vitro. Mol. Pharmacol., 65 (3): 630-8. [PMID:14978241]
31. Kaushal V, Koeberle PD, Wang Y, Schlichter LC. (2007) The Ca2+-activated K+ channel KCNN4/KCa3.1 contributes to microglia activation and nitric oxide-dependent neurodegeneration. J. Neurosci., 27 (1): 234-44. [PMID:17202491]
32. Khanna R, Chang MC, Joiner WJ, Kaczmarek LK, Schlichter LC. (1999) hSK4/hIK1, a calmodulin-binding KCa channel in human T lymphocytes. Roles in proliferation and volume regulation. J. Biol. Chem., 274 (21): 14838-49. [PMID:10329683]
33. Khanna R, Roy L, Zhu X, Schlichter LC. (2001) K+ channels and the microglial respiratory burst. Am. J. Physiol., Cell Physiol., 280 (4): C796-806. [PMID:11245596]
34. King B, Rizwan AP, Asmara H, Heath NC, Engbers JD, Dykstra S, Bartoletti TM, Hameed S, Zamponi GW, Turner RW. (2015) IKCa channels are a critical determinant of the slow AHP in CA1 pyramidal neurons. Cell Rep, 11 (2): 175-82. [PMID:25865881]
35. Köhler R, Brakemeier S, Kühn M, Behrens C, Real R, Degenhardt C, Orzechowski HD, Pries AR, Paul M, Hoyer J. (2001) Impaired hyperpolarization in regenerated endothelium after balloon catheter injury. Circ. Res., 89 (2): 174-9. [PMID:11463725]
36. Köhler R, Eichler I, Schönfelder H, Grgic I, Heinau P, Si H, Hoyer J. (2005) Impaired EDHF-mediated vasodilation and function of endothelial Ca-activated K channels in uremic rats. Kidney Int., 67 (6): 2280-7. [PMID:15882269]
37. Köhler R, Hoyer J. (2007) The endothelium-derived hyperpolarizing factor: insights from genetic animal models. Kidney Int., 72 (2): 145-50. [PMID:17457372]
38. Köhler R, Wulff H, Eichler I, Kneifel M, Neumann D, Knorr A, Grgic I, Kämpfe D, Si H, Wibawa J, Real R, Borner K, Brakemeier S, Orzechowski HD, Reusch HP, Paul M, Chandy KG, Hoyer J. (2003) Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis. Circulation, 108 (9): 1119-25. [PMID:12939222]
39. Logsdon NJ, Kang J, Togo JA, Christian EP, Aiyar J. (1997) A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes. J. Biol. Chem., 272 (52): 32723-6. [PMID:9407042]
40. Matteson DR, Deutsch C. (1984) K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion. Nature, 307 (5950): 468-71. [PMID:6320008]
41. Mauler F, Hinz V, Horváth E, Schuhmacher J, Hofmann HA, Wirtz S, Hahn MG, Urbahns K. (2004) Selective intermediate-/small-conductance calcium-activated potassium channel (KCNN4) blockers are potent and effective therapeutics in experimental brain oedema and traumatic brain injury caused by acute subdural haematoma. Eur. J. Neurosci., 20 (7): 1761-8. [PMID:15379997]
42. Neylon CB, Lang RJ, Fu Y, Bobik A, Reinhart PH. (1999) Molecular cloning and characterization of the intermediate-conductance Ca(2+)-activated K(+) channel in vascular smooth muscle: relationship between K(Ca) channel diversity and smooth muscle cell function. Circ. Res., 85 (9): e33-43. [PMID:10532960]
43. 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]
44. Ouadid-Ahidouch H, Roudbaraki M, Delcourt P, Ahidouch A, Joury N, Prevarskaya N. (2004) Functional and molecular identification of intermediate-conductance Ca(2+)-activated K(+) channels in breast cancer cells: association with cell cycle progression. Am. J. Physiol., Cell Physiol., 287 (1): C125-34. [PMID:14985237]
45. Parihar AS, Coghlan MJ, Gopalakrishnan M, Shieh CC. (2003) Effects of intermediate-conductance Ca2+-activated K+ channel modulators on human prostate cancer cell proliferation. Eur. J. Pharmacol., 471 (3): 157-64. [PMID:12826234]
46. 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]
47. Peña TL, Chen SH, Konieczny SF, Rane SG. (2000) Ras/MEK/ERK Up-regulation of the fibroblast KCa channel FIK is a common mechanism for basic fibroblast growth factor and transforming growth factor-beta suppression of myogenesis. J. Biol. Chem., 275 (18): 13677-82. [PMID:10788486]
48. Rapetti-Mauss R, Lacoste C, Picard V, Guitton C, Lombard E, Loosveld M, Nivaggioni V, Dasilva N, Salgado D, Desvignes JP et al.. (2015) A mutation in the Gardos channel is associated with hereditary xerocytosis. Blood, 126 (11): 1273-80. [PMID:26148990]
49. Rauer H, Lanigan MD, Pennington MW, Aiyar J, Ghanshani S, Cahalan MD, Norton RS, Chandy KG. (2000) Structure-guided transformation of charybdotoxin yields an analog that selectively targets Ca(2+)-activated over voltage-gated K(+) channels. J. Biol. Chem., 275 (2): 1201-8. [PMID:10625664]
50. Raychaudhuri SK, Wulff H, Raychaudhuri SP. (2016) KCa3.1(-/-) Mice Do Not Develop CIA: Regulatory Role for KCa3.1 in Autoimmune Arthritis. J. Cell. Physiol., 231 (11): 2313-4. [PMID:26910182]
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