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Target not currently curated in GtoImmuPdb
Target id: 381
Nomenclature: KCa2.1
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 | 543 | 19p13.11 | KCNN1 | potassium calcium-activated channel subfamily N member 1 | 10,14,16,23 |
Mouse | 5 | 1 | 537 | 8 B3.3 | Kcnn1 | potassium intermediate/small conductance calcium-activated channel, subfamily N, member 1 | 22 |
Rat | 6 | 1 | 536 | 16p14 | Kcnn1 | potassium calcium-activated channel subfamily N member 1 | 14,23 |
Database Links | |
Alphafold | Q92952 (Hs), Q9EQR3 (Mm), P70606 (Rn) |
ChEMBL Target | CHEMBL2369 (Hs), CHEMBL3743 (Rn) |
Ensembl Gene | ENSG00000105642 (Hs), ENSMUSG00000002908 (Mm), ENSRNOG00000029264 (Rn) |
Entrez Gene | 3780 (Hs), 84036 (Mm), 54261 (Rn) |
Human Protein Atlas | ENSG00000105642 (Hs) |
KEGG Gene | hsa:3780 (Hs), mmu:84036 (Mm), rno:54261 (Rn) |
OMIM | 602982 (Hs) |
Pharos | Q92952 (Hs) |
RefSeq Nucleotide | NM_002248 (Hs), NM_032397 (Mm), NM_019313 (Rn) |
RefSeq Protein | NP_002239 (Hs), NP_115773 (Mm), NP_062186 (Rn) |
UniProtKB | Q92952 (Hs), Q9EQR3 (Mm), P70606 (Rn) |
Wikipedia | KCNN1 (Hs) |
Associated Proteins | ||||||||||||||||||||
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Functional Characteristics | |
SKCa |
Ion Selectivity and Conductance | ||||||
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Voltage Dependence Comments |
KCa2.1 is voltage independent. |
Download all structure-activity data for this target as a CSV file
Activators | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Activator Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Homomeric rat KCa2.1 channels are not functional, in contrast to human KCa2.1 [1,9,14]. Co-expression with rat KCa2.2 [1] or exchanging the C-terminus of rKCa2.1 with hKCa2.1 [9] produces functional channels that are less sensitive to apamin or apamin-insensitive [1,9]. NS309 and EBIO increase the calcium-sensitivity of both KCa2 and KCa3.1 channels [18,28]. (-)-CM-TPMF and GW542573X display 10-fold selectivity for KCa2.1 over KCa2.2 and KCa2.3 [12-13]. |
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 [26]. (-)-B-TPMF is a close structural analog of the KCa2.1 activator (= positive gating modulator) (-)-CM-TPMF; (-)-B-TPMF is more than 30-fold selective for KCa2.1 over KCa2.2 and KCa2.3 [12]. |
Channel Blockers | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Channel Blocker Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
An extensive review of KCa2 and KCa3 channel pharmacology can be found in [31]. For shorter more recent reviews see [7,32]. |
Tissue Distribution | ||||||||
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Functional Assays | ||||||||||
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Physiological Functions | ||||||||
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Gene Expression and Pathophysiology | ||||||||||||
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Biologically Significant Variant Comments |
There are four splice variants in humans, three of which show diminished calmodulin binding [34]. In the mouse there are 32 possible splice variants, 20 of which have been been detected in mouse brain. These 20 variants encoded 16 KCa2.1 protein variants, with most c-terminal variants failing to bind calmodulin [22]. |
General Comments |
The KCa2 channels have been proposed as potential targets for the treatment of ataxia, epilepsy, memory disorders, pain and possibly schizophrenia and Parkinson's disease [2,15,31]. |
1. Benton DC, Monaghan AS, Hosseini R, Bahia PK, Haylett DG, Moss GW. (2003) Small conductance Ca2+-activated K+ channels formed by the expression of rat SK1 and SK2 genes in HEK 293 cells. J Physiol (Lond.), 553 (Pt 1): 13-9. [PMID:14555714]
2. 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]
3. Boettger MK, Till S, Chen MX, Anand U, Otto WR, Plumpton C, Trezise DJ, Tate SN, Bountra C, Coward K et al.. (2002) Calcium-activated potassium channel SK1- and IK1-like immunoreactivity in injured human sensory neurones and its regulation by neurotrophic factors. Brain, 125 (Pt 2): 252-63. [PMID:11844726]
4. 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]
5. Bond CT, Maylie J, Adelman JP. (2005) SK channels in excitability, pacemaking and synaptic integration. Curr Opin Neurobiol, 15 (3): 305-11. [PMID:15922588]
6. 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]
7. 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]
8. Church TW, Weatherall KL, Corrêa SA, Prole DL, Brown JT, Marrion NV. (2015) Preferential assembly of heteromeric small conductance calcium-activated potassium channels. Eur J Neurosci, 41 (3): 305-15. [PMID:25421315]
9. D'hoedt D, Hirzel K, Pedarzani P, Stocker M. (2004) Domain analysis of the calcium-activated potassium channel SK1 from rat brain. Functional expression and toxin sensitivity. J Biol Chem, 279 (13): 12088-92. [PMID:14761961]
10. 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]
11. 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]
12. Hougaard C, Hammami S, Eriksen BL, Sørensen US, Jensen ML, Strøbæk D, Christophersen P. (2012) Evidence for a common pharmacological interaction site on K(Ca)2 channels providing both selective activation and selective inhibition of the human K(Ca)2.1 subtype. Mol Pharmacol, 81 (2): 210-9. [PMID:22046005]
13. Hougaard C, Jensen ML, Dale TJ, Miller DD, Davies DJ, Eriksen BL, Strøbaek D, Trezise DJ, Christophersen P. (2009) Selective activation of the SK1 subtype of human small-conductance Ca2+-activated K+ channels by 4-(2-methoxyphenylcarbamoyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (GW542573X) is dependent on serine 293 in the S5 segment. Mol Pharmacol, 76 (3): 569-78. [PMID:19515965]
14. 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]
15. 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]
16. Litt M, LaMorticella D, Bond CT, Adelman JP. (1999) Gene structure and chromosome mapping of the human small-conductance calcium-activated potassium channel SK1 gene (KCNN1). Cytogenet Cell Genet, 86 (1): 70-3. [PMID:10516439]
17. 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]
18. 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]
19. Sankaranarayanan A, Raman G, Busch C, Schultz T, Zimin PI, Hoyer J, Köhler R, Wulff H. (2009) Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure. Mol Pharmacol, 75 (2): 281-95. [PMID:18955585]
20. Shah M, Haylett DG. (2000) The pharmacology of hSK1 Ca2+-activated K+ channels expressed in mammalian cell lines. Br J Pharmacol, 129 (4): 627-30. [PMID:10683185]
21. Shakkottai VG, Regaya I, Wulff H, Fajloun Z, Tomita H, Fathallah M, Cahalan MD, Gargus JJ, Sabatier JM, Chandy KG. (2001) Design and characterization of a highly selective peptide inhibitor of the small conductance calcium-activated K+ channel, SkCa2. J Biol Chem, 276 (46): 43145-51. [PMID:11527975]
22. Shmukler BE, Bond CT, Wilhelm S, Bruening-Wright A, Maylie J, Adelman JP, Alper SL. (2001) Structure and complex transcription pattern of the mouse SK1 K(Ca) channel gene, KCNN1. Biochim Biophys Acta, 1518 (1-2): 36-46. [PMID:11267657]
23. Stocker M. (2004) Ca(2+)-activated K+ channels: molecular determinants and function of the SK family. Nat Rev Neurosci, 5 (10): 758-70. [PMID:15378036]
24. Stocker M, Hirzel K, D'hoedt D, Pedarzani P. (2004) Matching molecules to function: neuronal Ca2+-activated K+ channels and afterhyperpolarizations. Toxicon, 43 (8): 933-49. [PMID:15208027]
25. Stocker M, Pedarzani P. (2000) Differential distribution of three Ca(2+)-activated K(+) channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system. Mol Cell Neurosci, 15 (5): 476-93. [PMID:10833304]
26. Strøbaek D, Hougaard C, Johansen TH, Sørensen US, Nielsen EØ, Nielsen KS, Taylor RD, Pedarzani P, Christophersen P. (2006) Inhibitory gating modulation of small conductance Ca2+-activated K+ channels by the synthetic compound (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) reduces afterhyperpolarizing current in hippocampal CA1 neurons. Mol Pharmacol, 70 (5): 1771-82. [PMID:16926279]
27. Strøbaek D, Jørgensen TD, Christophersen P, Ahring PK, Olesen SP. (2000) Pharmacological characterization of small-conductance Ca(2+)-activated K(+) channels stably expressed in HEK 293 cells. Br J Pharmacol, 129 (5): 991-9. [PMID:10696100]
28. Strøbaek D, Teuber L, Jørgensen TD, Ahring PK, Kjaer K, Hansen RS, Olesen SP, Christophersen P, Skaaning-Jensen B. (2004) Activation of human IK and SK Ca2+ -activated K+ channels by NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime). Biochim Biophys Acta, 1665 (1-2): 1-5. [PMID:15471565]
29. Tuteja D, Xu D, Timofeyev V, Lu L, Sharma D, Zhang Z, Xu Y, Nie L, Vázquez AE, Young JN et al.. (2005) Differential expression of small-conductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. Am J Physiol Heart Circ Physiol, 289 (6): H2714-23. [PMID:16055520]
30. Weatherall KL, Goodchild SJ, Jane DE, Marrion NV. (2010) Small conductance calcium-activated potassium channels: from structure to function. Prog Neurobiol, 91 (3): 242-55. [PMID:20359520]
31. 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. [PMID:17584055]
32. Wulff H, Köhler R. (2013) Endothelial small-conductance and intermediate-conductance KCa channels: an update on their pharmacology and usefulness as cardiovascular targets. J Cardiovasc Pharmacol, 61 (2): 102-12. [PMID:23107876]
33. Xia XM, Fakler B, Rivard A, Wayman G, Johnson-Pais T, Keen JE, Ishii T, Hirschberg B, Bond CT, Lutsenko S et al.. (1998) Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature, 395 (6701): 503-7. [PMID:9774106]
34. Zhang BM, Kohli V, Adachi R, López JA, Udden MM, Sullivan R. (2001) Calmodulin binding to the C-terminus of the small-conductance Ca2+-activated K+ channel hSK1 is affected by alternative splicing. Biochemistry, 40 (10): 3189-95. [PMID:11258935]