KCa2.2 channels

Channel name KCa2.2
Description Small-conductance, calcium-activated potassium channel; activated via a calmodulin-dependent mechanism
Other names SK2,1 SKCa2
Molecular information Human: 579aa, NM_021614 (transcript variant 1), chr. 5q22.3,2 KCNN2
Mouse: 574aa, NM_080465, chr. 18
Rat: 580aa, NM_019314, chr. 18q11
Associated subunits Calmodulin tightly complexed to C terminus,3,4 protein kinase CK2 and protein phosphatase 2A23
Functional assays Electrophysiology
Current Small-conductance, calcium-activated K+ current in neurones possibly underlies the medium IAHP current in hippocampal neurones
Conductance 9.9pS (symmetric K+), 2–3pS (normal Ringer)5
Ion selectivity K+-selective5
Activation Activated by intracellular Ca2+ (Kd = 0.6 μM, nH = 4)5
Inactivation None
Activators EBIO,6 chlorzoxazone, zoxazolamine,7 NS309 (30 nM),8 riluzole (2 μM)
Gating inhibitors None
Blockers Tamapin (24 pM),9 apamin (60–200 pM),1,10 leiurotoxin/scyllatoxin (200 pM), leiuritoxin-Dab7 (3.8 nM), PO5 (22 nM), Tskappa (80 nM), Pi1-OH (> 1 μM), Pi1-NH2 (100 nM), and maurotoxin (1 μM),11 UCL1684 (250pM),12 tubocurarine (5 μM)10; with micromolar affinity: amitriptyline, carbamazepine, chlorpromazine, cyproheptadine, fluoxetine, imipramine, tacrine, trifluperazine,13 biciculline (1.1 μM)22
Radioligands [125I]apamin14
Channel distribution Brain (spinal cord > hippocampus, cerebellum > amygdala > foetal brain > corpus callosum, thalamus, caudate nucleus, substantia nigra),15 pituitary gland, melanocyte, melanoma, germ cell tumor, prostate, oligodendroglioma, lung, Jurkat T cells,16 liver, heart,17 skeletal muscle, myometrium
Physiological functions Underlies the medium afterhyperpolarization in vertebrate neurones18,19
Mutations and pathophysiology Dominant-negative suppression of KCa2.2 channels in deep cerebellar nuclei in a transgenic mouse causes cerebellar ataxia20
Pharmacological significance Modulators of SK channel subtypes may have potential use in the treatment of myotonic muscular dystrophy, gastrointestinal dysmotility, memory disorders, epilepsy, narcolepsy, and alcohol intoxication21; KCa2.2 openers have been proposed for the treatment of cerebellar ataxia20
Comments The channel is voltage-independent and weakly rectifying; shared intron-exon structure with members of the KCa2 and KCa3 subfamilies2
  • aa, amino acids; chr., chromosome; NS309, 6,7-dichloro-1H-indole-2,3-dione-3-oxime; SK, small-conductance K+ channel; EBIO, 1-ethyl-2-benzimidazolinone; UCL1684, 6,12,19,20,25,26-hexahycro-5,27:13,18:21,24-trietheno-11,7-methano-7H-dibenzo [b,n] [1,5,12,16] tetraazacyclotricosine-5,13-dilum ditrifluoroacetate.

  • 1. Kohler M, Hirschberg B, Bond CT, Kinzie JM, Marrion NV, Maylie J, and Adelman JP (1996) Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273:1709-1714

  • 2. Ghanshani S, Wulff H, Miller MJ, Rohm H, Neben A, Gutman GA, Cahalan MD, and Chandy KG (2000) Up-regulation of the IKCa1 potassium channel during T-cell activation. Molecular mechanism and functional consequences. J Biol Chem 275:37137-37149

  • 3. 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 (Lond) 395:503-507

  • 4. Schumacher MA, Rivard AF, Bachinger HP, and Adelman JP (2001) Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin. Nature (Lond) 410:1120-1124

  • 5. Hirschberg B, Maylie J, Adelman JP, and Marrion NV (1998) Gating of recombinant small-conductance Ca-activated K+ channels by calcium. J Gen Physiol 111:565-581

  • 6. Pedarzani P, Mosbacher J, Rivard A, Cingolani LA, Oliver D, Stocker M, Adelman JP, and Fakler B (2001) Control of electrical activity in central neurons by modulating the gating of small-conductance Ca2+-activated K+ channels. J Biol Chem 276:9762-9769

  • 7. Cao Y, Dreixler JC, Roizen JD, Roberts MT, and Houamed KM (2001) Modulation of recombinant small-conductance Ca2+-activated K+ channels by the muscle relaxant chlorzoxazone and structurally related compounds. J Pharmacol Exp Ther 296:683-689

  • 8. Strobaek D, Teuber L, Jorgensen TD, Ahring PK, Kaer K, Hansen RS, Olesen SP, Christophersen P, and Skaaning-Jensen B (2004) Activation of human IK and SK Ca2+-activated K+ channels by NS309 (6,7-dichloro-1H-indole-2,3-dione3-oxime). Biochim Biophys Acta 1665:1-5

  • 9. 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 venompeptide from the Indian red scorpion (Mesobuthus tamulus) that targets small conductance Ca2+-activated K+ channels and after hyperpolarization currents in central neurons. J Biol Chem 277:46101-46109

  • 10. Ishii TM, Maylie J, and Adelman JP (1997) Determinants of apamin and d-tubocurarine block in SK potassium channels. J Biol Chem 272:23195-23200

  • 11. Shakkottai VG, Regaya I, Wulff H, Fajloun Z, Tomita H, Fathallah M, Cahalan MD, Gargus JJ, Sabatier JM, and Chandy KG (2001) Design and characterization of a highly selective peptide inhibitor of the small conductance calcium-activated K+ channel, SKCa2. J Biol Chem 276:43145-43151

  • 12. Fanger CM, Rauer H, Neben AL, Miller MJ, Rauer H, Wulff H, Rosa JC, Ganellin CR, Chandy KG, and Cahalan MD (2000) Calcium-activated potassium channels sustain calcium signaling in T lymphocytes. Selective blockers and manipulated channel expression levels. J Biol Chem 276: 12249-12256

  • 13. Dreixler JC, Bian J, Cao Y, Roberts MT, Roizen JD, and Houamed KM (2000) Block of rat brain recombinant SK channels by tricyclic antidepressants and related compounds. Eur J Pharmacol 401:1-7

  • 14. Romey G, Hugues M, Schmid-Antomarchi H, and Lazdunski M (1984) Apamin: a specific toxin to study a class of Ca2+-dependent K+ channels. J Physiol (Paris) 79:259-264

  • 15. Stocker M and Pedarzani P (2000) Differential distribution of three Ca2+-activated K+ channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system. Mol Cell Neurosci 15:476-493

  • 16. Jager H, Adelman JP, and Grissmer S (2000) SK2 encodes the apamin-sensitive Ca (2+)-activated K(+) channels in the human leukemic T cell line, Jurkat. FEBS Lett 469:196-202

  • 17. Xu Y, Tuteja D, Zhang Z, Xu D, Zhang Y, Rodriguez J, Nie L, Tuxson HR, Young JN, Glatter KA, et al. (2003) Molecular identification and functional roles of a Ca2+-activated K+ channel in human and mouse hearts. J Biol Chem 278:49085-49094

  • 18. Villalobos C, Shakkottai VG, Chandy KG, Michelhaugh SK, and Andrade R (2004) SKCa channels mediate the medium but not the slow calcium-activated afterhyperpolarization in cortical neurons. J Neurosci 24:3537-3542

  • 19. Bond CT, Herson PS, Strassmaier T, Hammond R, Stackman R, Maylie J, and Adelman JP (2004) Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents. J Neurosci 24:5301-5306

  • 20. Shakkottai VG, Chou CH, Oddo S, Sailer CA, Knaus HG, Gutman GA, Barish ME, LaFerla FM, and Chandy KG (2004) Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. J Clin Investig 113:582-590

  • 21. Coghlan MJ, Carrol WA, and Gopalakrishnan M (2001) Recent developments in the biology and medicinal chemistry of potassium channel modulators: update from a decade of progress. J Med Chem 44:1-27

  • 22. Khawaled R, Bruening-Wright A, Adelman JP, and Maylie J (1999) Bicuculline block of small-conductance calcium-activated potassium channels. Pflugers Arch Eur J Physiol 438:314-321

  • 23. 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 Ca2+-activated K+ channels and regulates channel gating. Neuron 43:847-858