TABLE 5

KCa2.3 channels

Channel name KCa2.3
Description Small-conductance, calcium-activated potassium channel activated via a calmodulin-dependent mechanism
Other names SK3,1 hKCa3, SKCa32
Molecular information Human: 736aa, NM_002249 (transcript variant 1), chr. 1q21.3,3,4 KCNN3
Mouse: 731aa, NM_080466, chr. 3
Rat: 732aa, NM_019315, chr. 2q34
Associated subunits Calmodulin tightly complexed to C terminus5,6
Functional assays Patch-clamp
Current Small-conductance, calcium-activated K+ current in neurones7
Conductance Not determined
Ion selectivity K+-selective
Activation Activated by intracellular Ca2+ (Kd = 0.6 uM)8
Inactivation None
Activators EBIO, riluzole (3 μM),9 NS309 (30 nM)10
Gating inhibitors None
Blockers Leiurotoxin/scyllatoxin (1.1 nM), apamin (10 nM), PO5 (25 nM), Tskappa (197 nM), Pi1-OH (330 nM), and Pi1-NH2 (250 nM),11 UCL1684 (9.5 nM)12; with micromolar affinity: bicuculline,9 amitriptyline, fluoxetine, desipramine, imipramine, nortriptyline, fluphenazine, promethazine, chlorpromazine
Radioligands [125I]apamine13
Channel distribution Brain (substantia nigra > amygdala, caudate nucleus, thalamus, hippocampus, ventral tegmental area, cerebellum, spinal cord > corpus callosum, foetal brain), lymphocytes (germinal center B cells, tonsillar B cells, Burkitt's lymphoma, microglia), skeletal muscle (increased denervated muscle, myotonic dystrophy), myometrium, prostate, kidney, heart, pituitary gland, liver, pancreas, colon, germinal cells, head, neck, ovary, vascular endothelium1,3,14,15,16,17,18,19
Physiological functions Involved in the afterhyperpolarization in vertebrate neurones7,17 (any newer comments on this?)
Mutations and pathophysiology Longer polyglutamine repeats are over-represented in schizophrenic (especially negative-symptom form)2,18 individuals and in patients with anorexia nervosa20 and spinocerebellar ataxia21; a four-base deletion has been found in a patient with schizophrenia22 that truncates the protein just before the S1 segment and causes dominant-negative suppression of endogenous SK channels23; protein and mRNA levels are increased in skeletal muscle following denervation24 and in patients with myotonic muscular dystrophy25; involved in the endothelium-mediated vasodilation (EDHF response)19; conditional knockout of KCa2.3 leads to hypertension26 and bladder instability27
Pharmacological significance Modulators of SK channel subtypes may have potential use in the treatment of myotonic muscular dystrophy, gastrointestinal dysmotility, memory disorders, epilepsy, narcolepsy, hypertension,26 and urinary incontinence27
Comments Channel is voltage-independent

  • aa, amino acids; chr., chromosome; NS309, 6,7-dichloro-1H-indole-2,3-dione-3-oxime; EDHF, endothelium-derived hyperpolarizing factor; EBIO, 1-ethyl-2-benzimidazolinone; SK, small-conductance K+ channel; 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. Chandy KG, Fantino E, Wittekindt O, Kalman K, Tong LL, Ho TH, Gutman GA, Crocq MA, Ganguli R, Nimgaonkar V, et al. (1998) Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder? Mol Psychiatry 3:32-37

  • ↵3. Dror V, Shamir E, Ghanshani S, Kimhi R, Swartz M, Barak Y, Weizman R, Avivi L, Litmanovitch T, Fantino E, et al. (1999) hKCa3/KCNN3 potassium channel gene: association of longer CAG repeats with schizophrenia in Israeli Ashkenazi Jews, expression inhuman tissues and localization to chromosome 1q21. Mol Psychiatry 4:254-260

  • ↵4. Sun G, Tomita H, Shakkottai VG, and Gargus JJ (2001) Genomic organization and promoter analysis of human KCNN3 gene. J Hum Genet 46:463-470

  • ↵5. 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

  • ↵6. Fanger CM, Ghanshani S, Logsdon NJ, Rauer H, Kalman K, Zhou J, Beckingham K, Chandy KG, Cahalan MD, and Aiyar J (1999) Calmodulin mediates calcium-dependent activation of the intermediate conductance KCa channel, IKCa1. J Biol Chem 274:5746-5754

  • ↵7. Wolfart J, Neuhoff H, Franz O, and Roeper J (2001) Differential expression of the small-conductance, calcium-activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons. J Neurosci 21:3443-3456

  • ↵8. Barfod ET, Moore AL, and Lidofsky SD (2001) Cloning and functional expression of a liver isoform of the small conductance Ca2+-activated K+ channel SK3. Am J Physiol Cell Physiol 280:C836-C842

  • ↵9. Grunnet M, Jespersen T, Angelo K, Frokjaer-Jensen C, Klaerke DA, Olesen SP, and Jensen BS (2001) Pharmacological modulation of SK3 channels. Neuropharmacology 40:879-887

  • ↵10. 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

  • ↵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. 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

  • ↵14. 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

  • ↵15. Pribnow D, Johnson-Pais T, Bond CT, Keen J, Johnson RA, Janowsky A, Silvia C, Thayer M, Maylie J, and Adelman JP (1999) Skeletal muscle and small-conductance calcium-activated potassium channels. Muscle and Nerve 22:742-750

  • ↵16. UniGene Cluster Hs0.89230; Online Mendelian Inheritance in Man (OMIM) no. 602983

  • ↵17. Hosseini R, Benton DC, Dunn PM, Jenkinson DH, and Moss GW (2001) SK3 is an important component of K (+) channels mediating the after-hyperpolarization in cultured rat SCG Neurones. J Physiol 535:323-334

  • ↵18. Cardno AG, Bowen T, Guy CA, Jones LA, McCarthy G, Williams NM, Murphy KC, Spurlock G, Gray M, Sanders RD, et al. (1999) CAG repeat length in the hKCa3 gene and symptom dimensions in schizophrenia. Biol Psychiatry 45:1592-1596

  • ↵19. Burnham MP, Bychkov R, Feletou M, Richards GR, Vanhoutte PM, Weston AH, and Edwards G (2002) Characterization of an apamin-sensitive small-conductance Ca2+-activated K+ channel in porcine coronary artery endothelium: relevance to EDHF. Br J Pharmacol 135:1133-1143

  • ↵20. Koronyo-Hamaoui M, Danziger Y, Frisch A, Stein D, Leor S, Laufer N, Carel C, Fennig S, Minoumi M, Apter A, et al. (2002) Association between anorexia nervosa and the hsKCa3 gene: a family-based and case control study. Mol Psychiatry 7:82-85

  • ↵21. Figueroa KP, Chan P, Schols L, Tanner C, Riess O, Perlman SL, Geschwind DH, and Pulst SM (2001) Association of moderate polyglutamine tract expansions in the slow calcium-activated potassium channel type 3 with ataxia. Arch Neurol 58:1649-1653

  • ↵22. Bowen T, Williams N, Norton N, Spurlock G, Wittekindt OH, Morris-Rosendahl DJ, Williams H, Brzustowicz L, Hoogendoorn B, Zammit S, Jones G, et al. (2001) Mutation screening of the KCNN3 gene reveals a rare frame shift mutation. Mol Psychiatry 6:259-260

  • ↵23. Miller MJ, Rauer H, Tomita H, Rauer H, Gargus JJ, Gutman GA, Cahalan MD, and Chandy KG (2001) Nuclear localization and dominant-negative suppression by a mutant SKCa3 N-terminal channel fragment identified in a patient with schizophrenia. J Biol Chem 276:27753-27756

  • ↵24. Neelands TR, Herson PS, Jacobson D, Adelman JP, and Maylie J (2001) Small-conductance calcium-activated potassium currents in mouse hyperexcitable denervated skeletal muscle. J Physiol 536:397-407

  • ↵25. Kimura T, Takahashi MP, Okuda Y, Kaido M, Fujimura H, Yanagihara T, and Sakoda S (2000) The expression of ion channel mRNAs in skeletal muscles from patients with myotonic muscular dystrophy. Neurosci Lett 295:93-96

  • ↵26. Taylor MS, Bonev AD, Gross TP, Eckman DM, Brayden JE, Bond CT, Adelman JP, and Nelson MT (2003) Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure. Circ Res 93:124-131

  • ↵27. Herrera GM, Pozo MJ, Zvara P, Petkov GV, Bond CT, Adelman JP, and Nelson MT (2003) Urinary bladder instability induced by selective suppression of the murine small conductance calcium-activated potassium (SK3) channel. J Physiol 551:893-903