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Gene Review

KCNN3  -  potassium channel, calcium activated...

Homo sapiens

Synonyms: K3, KCa2.3, SK3, SKCA3, SKCa 3, ...
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Disease relevance of KCNN3

  • The small-conductance calcium-activated K(+) channel SK3 (SKCa3/KCNN3) regulates electrical excitability and neurotransmitter release in monoaminergic neurons, and has been implicated in schizophrenia, ataxia and anorexia nervosa [1].
  • CONCLUSION: This association study provides no evidence that length variations of the second polyglutamine array in the N-terminus of the KCNN3 channel exert an effect in the pathogenesis of migraine [2].
  • Pharmacological and molecular characterisation of SK3 channels in the TE671 human medulloblastoma cell line [3].
  • Distribution of Ca2+-activated K channels, SK2 and SK3, in the normal and Hirschsprung's disease bowel [4].
  • METHODS: Given this role of ion channels in migraine, we assessed the potassium channel KCNN3 as a candidate gene for common migraine [5].

Psychiatry related information on KCNN3


High impact information on KCNN3

  • We have combined solid-state NMR, x-ray fiber diffraction, and atomic force microscopy to reveal the 3D structure of amyloid protofilament-like fibrils formed by a 22-residue K3 peptide (Ser(20)-Lys(41)) of beta(2)-microglobulin, a protein responsible for dialysis-related amyloidosis [10].
  • Heterologously expressed SK4, but not SK3, also shows this behavior [11].
  • Since both the hyper-stimulation of K(+) efflux and cell death were reduced by the highly specific SK inhibitor apamin, we suggest that increased expression of SK3 has a critical role in the increased Ca(2+)-induced fragility in DM1 cells [12].
  • Finally, mutation of this conserved lysine in rat SK3 similarly resulted in a channel that failed to correctly traffic to the plasma membrane [13].
  • Two small conductance, calcium-activated potassium channels (SK channels), SK2 and SK3, have been shown to contribute to the afterhyperpolarization (AHP) and to shape the firing behavior in neurons for example in the hippocampal formation, the dorsal vagal nucleus, the subthalamic nucleus, and the cerebellum [14].

Chemical compound and disease context of KCNN3

  • Riluzole, a potent neuroprotective drug with anti-ischemic, anticonvulsant and sedative effects currently used in the treatment of amyotrophic lateral sclerosis, activates SK3 channels at concentrations of 3 microM and above [15].

Biological context of KCNN3

  • FISH analysis shows that hKCa3/KCNN3 is located on chromosome 1q21 [16].
  • CONCLUSIONS: Our results support the hypothesis that a contribution of the KCNN3 gene to genetic susceptibility to major psychosis and their phenotypic polymorphism may be related to the difference of allele length rather than to the number of CAG repeats [7].
  • The KCNN3 gene spans over 163.1 kb and is composed of eight exons and seven introns [17].
  • To set the stage for a further functional evaluation of KCNN3, we defined the nature of the genomic locus in the size, structure, and sequence of its introns and exons and the function of potential upstream regulatory regions [17].
  • The KCNN3 cDNA sequence contains two stretches of CAG trinucleotide repeats encoding two separate polyglutamine segments near the N-terminus of this channel protein [18].

Anatomical context of KCNN3


Associations of KCNN3 with chemical compounds

  • Tricyclic antidepressants such as desipramine, imipramine and nortriptyline as well as phenothiazines such as fluphenazine, promethazine, chlorpromazine and trifluoperazine blocked the hSK3 channel with micromolar potencies [19].
  • Considering the N-C interaction in yeast, we conclude that the sensitivity of SK3 channels to 1-EBIO was modified by N-C interactions with SK3N_299 [21].
  • In addition, the interaction in SK3 was independent of the length of the polymorphic glutamine repeat in the N-terminus of SK3 [21].
  • Replacement of Thr(250) or Val(275) in IKCa1 with the corresponding SKCa3 residues selectively abolished triarylmethane sensitivity without affecting the affinity of the channel for tetraethylammonium, charybdotoxin, and nifedipine [23].
  • They were both blocked by tetraethylammonium (hSK3, Kd=2.2 mM; hSK3_ex4, 2.6 mM) and showed similar permeabilities relative to K+ for Cs+ (hSK3, 0.17 +/- 0.04, n=3; hSK3_ex4, 0.17 +/- 0.05, n=3) and Rb+ (hSK3, 0.79 +/- 0.04, n=3; hSK3_ex4, 0.8 +/- 0.07, n=3) [24].

Co-localisations of KCNN3


Other interactions of KCNN3

  • CAG repeat polymorphisms in KCNN3 (HSKCa3) and PPP2R2B show no association or linkage to schizophrenia [25].
  • KCNN3 is a neuronal small conductance calcium-activated potassium channel gene that contains two polyglutamine tracts, encoded by polymorphic CAG repeats in the gene [2].
  • In this report, we tested the hypothesis of an association between longer alleles of CAG repeat in the KCNN3 gene and schizophrenia in 20 families with clinical evidence for anticipation and in 151 unrelated schizophrenic cases [26].
  • In contrast, full-length SKCa3, SKCa2, and IKCa1 polypeptides are all excluded from the nucleus and express as functional channels [27].
  • The strong N-C and N-N interaction was specific for SK3 and could not be observed for SK1 and SK2 [21].

Analytical, diagnostic and therapeutic context of KCNN3

  • METHODS: CAG/CTG repeat distribution in KCNN3, CTG 18.1 and ERDA1 was examined and the copy number of ligation product in repeat expansion detection (RED) was measured in Korean bipolar patients in comparison to ethnically matched healthy controls [28].
  • This result was confirmed by direct recordings of SK3 currents using the whole-cell patch-clamp technique [19].
  • RESULTS: RT-PCR analysis showed strong expression of SK2 and SK3 mRNA in the normal human bowel and significantly reduced SK3 expression in the aganglionic bowel (P <.05) [4].
  • In the present study, we performed several meta-analyses to evaluate the pooled evidence for association with CAG-repeat length of KCNN3 derived from case-control and family-based studies of both disorders [29].
  • The present study extends the analysis of KCNN3 allele distribution to a larger series of AN female patients and control groups, incorporating information on ethnicity and co-morbidities associated with AN [30].


  1. Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia. Tomita, H., Shakkottai, V.G., Gutman, G.A., Sun, G., Bunney, W.E., Cahalan, M.D., Chandy, K.G., Gargus, J.J. Mol. Psychiatry (2003) [Pubmed]
  2. Association analysis of a highly polymorphic CAG Repeat in the human potassium channel gene KCNN3 and migraine susceptibility. Curtain, R., Sundholm, J., Lea, R., Ovcaric, M., MacMillan, J., Griffiths, L. BMC Med. Genet. (2005) [Pubmed]
  3. Pharmacological and molecular characterisation of SK3 channels in the TE671 human medulloblastoma cell line. Carignani, C., Roncarati, R., Rimini, R., Terstappen, G.C. Brain Res. (2002) [Pubmed]
  4. Distribution of Ca2+-activated K channels, SK2 and SK3, in the normal and Hirschsprung's disease bowel. Piotrowska, A.P., Solari, V., Puri, P. J. Pediatr. Surg. (2003) [Pubmed]
  5. A highly polymorphic poly-glutamine stretch in the potassium channel KCNN3 in migraine. Mössner, R., Weichselbaum, A., Marziniak, M., Freitag, C.M., Lesch, K.P., Sommer, C., Meyer, J. Headache. (2005) [Pubmed]
  6. Association and linkage studies between bipolar affective disorder and the polymorphic CAG/CTG repeat loci ERDA1, SEF2-1B, MAB21L and KCNN3. Meira-Lima, I.V., Zhao, J., Sham, P., Pereira, A.C., Krieger, J.E., Vallada, H. Mol. Psychiatry (2001) [Pubmed]
  7. Association study of CAG repeats in the KCNN3 gene in Israeli patients with major psychosis. Ritsner, M., Amir, S., Koronyo-Hamaoui, M., Gak, E., Ziv, H., Halperin, T., Kitain, L., Navon, R. Psychiatr. Genet. (2003) [Pubmed]
  8. Association study of CAG repeats in the KCNN3 gene in Japanese patients with schizophrenia, schizoaffective disorder and bipolar disorder. Ujike, H., Yamamoto, A., Tanaka, Y., Takehisa, Y., Takaki, M., Taked, T., Kodama, M., Kuroda, S. Psychiatry research. (2001) [Pubmed]
  9. hKCNN3 which maps to chromosome 1q21 is not the causative gene in periodic catatonia, a familial subtype of schizophrenia. Stöber, G., Meyer, J., Nanda, I., Wienker, T.F., Saar, K., Jatzke, S., Schmid, M., Lesch, K.P., Beckmann, H. European archives of psychiatry and clinical neuroscience. (2000) [Pubmed]
  10. 3D structure of amyloid protofilaments of beta2-microglobulin fragment probed by solid-state NMR. Iwata, K., Fujiwara, T., Matsuki, Y., Akutsu, H., Takahashi, S., Naiki, H., Goto, Y. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  11. The hSK4 (KCNN4) isoform is the Ca2+-activated K+ channel (Gardos channel) in human red blood cells. Hoffman, J.F., Joiner, W., Nehrke, K., Potapova, O., Foye, K., Wickrema, A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  12. Increased SK3 expression in DM1 lens cells leads to impaired growth through a greater calcium-induced fragility. Rhodes, J.D., Monckton, D.G., McAbney, J.P., Prescott, A.R., Duncan, G. Hum. Mol. Genet. (2006) [Pubmed]
  13. Role of an S4-S5 linker lysine in the trafficking of the Ca(2+)-activated K(+) channels IK1 and SK3. Jones, H.M., Hamilton, K.L., Devor, D.C. J. Biol. Chem. (2005) [Pubmed]
  14. Domain analysis of the calcium-activated potassium channel SK1 from rat brain. Functional expression and toxin sensitivity. D'hoedt, D., Hirzel, K., Pedarzani, P., Stocker, M. J. Biol. Chem. (2004) [Pubmed]
  15. Pharmacological modulation of SK3 channels. Grunnet, M., Jespersen, T., Angelo, K., Frøkjaer-Jensen, C., Klaerke, D.A., Olesen, S.P., Jensen, B.S. Neuropharmacology (2001) [Pubmed]
  16. hKCa3/KCNN3 potassium channel gene: association of longer CAG repeats with schizophrenia in Israeli Ashkenazi Jews, expression in human tissues and localization to chromosome 1q21. Dror, V., Shamir, E., Ghanshani, S., Kimhi, R., Swartz, M., Barak, Y., Weizman, R., Avivi, L., Litmanovitch, T., Fantino, E., Kalman, K., Jones, E.G., Chandy, K.G., Gargus, J.J., Gutman, G.A., Navon, R. Mol. Psychiatry (1999) [Pubmed]
  17. Genomic organization and promoter analysis of human KCNN3 gene. Sun, G., Tomita, H., Shakkottai, V.G., Gargus, J.J. J. Hum. Genet. (2001) [Pubmed]
  18. Schizophrenia and polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene in Serbian population. Ivković, M., Ranković, V., Tarasjev, A., Orolicki, S., Damjanović, A., Paunović, V.R., Romac, S. Int. J. Neurosci. (2006) [Pubmed]
  19. Pharmacological characterisation of the human small conductance calcium-activated potassium channel hSK3 reveals sensitivity to tricyclic antidepressants and antipsychotic phenothiazines. Terstappen, G.C., Pula, G., Carignani, C., Chen, M.X., Roncarati, R. Neuropharmacology (2001) [Pubmed]
  20. 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. Chen, M.X., Gorman, S.A., Benson, B., Singh, K., Hieble, J.P., Michel, M.C., Tate, S.N., Trezise, D.J. Naunyn Schmiedebergs Arch. Pharmacol. (2004) [Pubmed]
  21. Interactions of N-Terminal and C-Terminal Parts of the Small Conductance Ca Activated K(+) Channel, hSK3. Frei, E., Spindler, I., Grissmer, S., Jager, H. Cell. Physiol. Biochem. (2006) [Pubmed]
  22. Small conductance Ca2+-activated K+ channels as targets of CNS drug development. Blank, T., Nijholt, I., Kye, M.J., Spiess, J. Current drug targets. CNS and neurological disorders. (2004) [Pubmed]
  23. Delineation of the clotrimazole/TRAM-34 binding site on the intermediate conductance calcium-activated potassium channel, IKCa1. Wulff, H., Gutman, G.A., Cahalan, M.D., Chandy, K.G. J. Biol. Chem. (2001) [Pubmed]
  24. An apamin- and scyllatoxin-insensitive isoform of the human SK3 channel. Wittekindt, O.H., Visan, V., Tomita, H., Imtiaz, F., Gargus, J.J., Lehmann-Horn, F., Grissmer, S., Morris-Rosendahl, D.J. Mol. Pharmacol. (2004) [Pubmed]
  25. CAG repeat polymorphisms in KCNN3 (HSKCa3) and PPP2R2B show no association or linkage to schizophrenia. Laurent, C., Niehaus, D., Bauché, S., Levinson, D.F., Soubigou, S., Pimstone, S., Hayden, M., Mbanga, I., Emsley, R., Deleuze, J.F., Mallet, J. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2003) [Pubmed]
  26. No evidence for involvement of KCNN3 (hSKCa3) potassium channel gene in familial and isolated cases of schizophrenia. Bonnet-Brilhault, F., Laurent, C., Campion, D., Thibaut, F., Lafargue, C., Charbonnier, F., Deleuze, J.F., Ménard, J.F., Jay, M., Petit, M., Frebourg, T., Mallet, J. Eur. J. Hum. Genet. (1999) [Pubmed]
  27. Nuclear localization and dominant-negative suppression by a mutant SKCa3 N-terminal channel fragment identified in a patient with schizophrenia. Miller, M.J., Rauer, H., Tomita, H., Rauer, H., Gargus, J.J., Gutman, G.A., Cahalan, M.D., Chandy, K.G. J. Biol. Chem. (2001) [Pubmed]
  28. CAG repeats of CTG18.1 and KCNN3 in Korean patients with bipolar affective disorder. Jin, D.K., Hwang, H.Z., Oh, M.R., Kim, J.S., Lee, M., Kim, S., Lim, S.W., Seo, M.Y., Kim, J.H., Kim, D.K. Journal of affective disorders. (2001) [Pubmed]
  29. CAG-repeat length in exon 1 of KCNN3 does not influence risk for schizophrenia or bipolar disorder: a meta-analysis of association studies. Glatt, S.J., Faraone, S.V., Tsuang, M.T. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2003) [Pubmed]
  30. CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: a case-control study of female patients and several ethnic groups in the Israeli Jewish population. Koronyo-Hamaoui, M., Gak, E., Stein, D., Frisch, A., Danziger, Y., Leor, S., Michaelovsky, E., Laufer, N., Carel, C., Fennig, S., Mimouni, M., Apter, A., Goldman, B., Barkai, G., Weizman, A. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2004) [Pubmed]
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