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KCa2.1

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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)

Contents:

Gene and Protein Information Click here for help
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
Previous and Unofficial Names Click here for help
SK1 | SKCa1 | small conductance calcium-activated potassium channel protein 1 | potassium channel, calcium activated intermediate/small conductance subfamily N alpha, member 1 | potassium intermediate/small conductance calcium-activated channel
Database Links Click here for help
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 Click here for help
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
calmodulin 23,33
Other Associated Proteins
Name References
Not determined
Functional Characteristics Click here for help
SKCa
Ion Selectivity and Conductance Click here for help
Species:  Human
Rank order:  K+ [9.2 pS]
References:  14
Voltage Dependence Comments
KCa2.1 is voltage independent.

Download all structure-activity data for this target as a CSV file go icon to follow link

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
EBIO Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist - - 2x10-3 -80.0 18,30
⤷ Conc range: 2x10-3 M [18,30]
Holding voltage: -80.0 mV
NS309 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist - - 3x10-8 - 1x10-7 -90.0 28,30
⤷ Conc range: 3x10-8 - 1x10-7 M [28,30]
Holding voltage: -90.0 mV
CM-TPMF Small molecule or natural product Hs Agonist 7.6 pEC50 - -80.0 12
⤷ pEC50 7.6 (EC50 2.4x10-8 M) [12]
Holding voltage: -80.0 mV
Ca2+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Agonist 6.2 – 6.5 pEC50 - -80.0 14,33
⤷ pEC50 6.2 – 6.5 (EC50 6x10-7 – 3x10-7 M) [14,33]
Holding voltage: -80.0 mV
SKA-20 Small molecule or natural product Hs Agonist 6.4 pEC50 - -80.0 19
⤷ pEC50 6.4 (EC50 4.3x10-7 M) [19]
Holding voltage: -80.0 mV
SKA-31 Small molecule or natural product Click here for species-specific activity table Hs Agonist 5.5 pEC50 - -80.0 19
⤷ pEC50 5.5 (EC50 2.9x10-6 M) [19]
Holding voltage: -80.0 mV
GW542573X Small molecule or natural product Hs Agonist 5.1 pEC50 - -80.0 13
⤷ pEC50 5.1 (EC50 8.2x10-6 M) [13]
Holding voltage: -80.0 mV
riluzole Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 4.7 pEC50 - -80.0 19
⤷ pEC50 4.7 (EC50 2.1x10-5 M) [19]
Holding voltage: -80.0 mV
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
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
UCL1684 Small molecule or natural product Click here for species-specific activity table Hs - 9.1 pIC50 - - 27,30
⤷ pIC50 9.1 (IC50 8x10-10 M) [27,30]
apamin Peptide Click here for species-specific activity table Hs - 7.9 – 8.5 pIC50 - - 20,24,27
⤷ pIC50 7.9 – 8.5 (IC50 1.2x10-8 – 3.3x10-9 M) [20,24,27]
Gating inhibitors Click here for help
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
B-TPMF Small molecule or natural product Hs Antagonist 7.5 pEC50 - -80.0 12
⤷ pEC50 7.5 (EC50 3.1x10-8 M) [12]
Holding voltage: -80.0 mV
NS8593 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 6.4 pIC50 - 0.0 26
⤷ pIC50 6.4 (IC50 4x10-7 M) [26]
Holding voltage: 0.0 mV
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
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
UCL1848 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.0 pIC50 - -80.0 20
⤷ pIC50 9.0 (IC50 1x10-9 M) [20]
Holding voltage: -80.0 mV
tamapin Peptide Hs Antagonist 7.4 pIC50 - -100.0 – 40.0 17
⤷ pIC50 7.4 (IC50 4x10-8 M) [17]
Holding voltage: -100.0 – 40.0 mV
leiurotoxin I Peptide Click here for species-specific activity table Hs Antagonist 6.5 – 7.1 pIC50 - -120.0 – 40.0 21,27
⤷ pIC50 6.5 – 7.1 (IC50 3x10-7 – 8x10-8 M) [21,27]
Holding voltage: -120.0 – 40.0 mV
dequalinium Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 6.4 pIC50 - -80.0 20,27
⤷ pIC50 6.4 (IC50 4x10-7 M) [20,27]
Holding voltage: -80.0 mV
Lei-Dab7 Peptide Click here for species-specific activity table Hs Antagonist 5.2 pIC50 - -120.0 – 40.0 21
⤷ pIC50 5.2 (IC50 6x10-6 M) [21]
Holding voltage: -120.0 – 40.0 mV
bicuculline Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 4.8 pIC50 - 80.0 27
⤷ pIC50 4.8 (IC50 1.6x10-5 M) [27]
Holding voltage: 80.0 mV
tubocurarine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 4.1 – 4.6 pIC50 - -100.0 – 80.0 14,20,27
⤷ pIC50 4.1 – 4.6 (IC50 8x10-5 – 2.5x10-5 M) [14,20,27]
Holding voltage: -100.0 – 80.0 mV
tetraethylammonium Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - 2.7 pIC50 - - 30
⤷ pIC50 2.7 [30]
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 Click here for help
Brain (cortex, hippocampus, amygdala, putamen, caudate nucleus, cerebellum, medulla, substantia nigra, thalamus), corpus callosum, spinal cord > ovary and testis.
Species:  Human
Technique:  RT-PCR
References:  6
Enteric neurons, small and medium sized cell bodies in the dorsal root ganglion.
Species:  Human
Technique:  Immunohistochemistry
References:  3,6
Brain, heart (atrium > ventricle), kidney, stomach, colon.
Species:  Mouse
Technique:  RT-PCR
References:  22,29
Brain (hippocampus, dentate gyrus, subiculum, anterior olfactory nucleus, olfactory tubercle, cortex, cerebellum).
Species:  Rat
Technique:  In situ hybridisation
References:  14
Brain and heart.
Species:  Rat
Technique:  Northern Blot
References:  14
Brain (olfactory system, neocortex, hippocampus, septum, amygdala, thalamus, habenula, hypothalamus, brain stem, cerebellum, ependyma).
Species:  Rat
Technique:  In situ hybridisation
References:  25
Functional Assays Click here for help
Patch-clamp recordings of mammalian cells transiently or stably transfected with hKCa2.1.
Species:  Human
Tissue:  HEK293 or COS-7 cells.
Response measured:  KCa2.1 current.
References:  1,9,17,20,24,27-28
Two-electrode voltage-clamp of Xenopus oocytes injected with hKCa2.1 mRNA.
Species:  Human
Tissue:  Xenopus oocytes.
Response measured:  KCa2.1 currents.
References:  14
Physiological Functions Click here for help
KCa2.1 is thought to be involved in medium after hyperpolarisation in various neurons. The KCa2.2 however, is sufficient to abolish apamin-sensitive currents in CA1 hippocampal neurons.
Species:  Mouse
Tissue:  Brain, in vitro work on coassembly with human clone.
References:  4-5,8,11,23-24,31
Gene Expression and Pathophysiology Click here for help
Decrease in KCa2.1 expression.
Tissue or cell type:  Injured DRG neurons.
Pathophysiology:  Suggested to increase excitability.
Species:  Human
Technique:  Immunohistochemistry
References:  3
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].

References

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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]

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