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Channelopathy of small- and intermediate-conductance Ca2+-activated K+ channels

Acta Pharmacologica Sinica volume 44, pages 259–267 (2023)Cite this article

Abstract

Small- and intermediate-conductance Ca2+-activated K+ (KCa2.x/KCa3.1 also called SK/IK) channels are gated exclusively by intracellular Ca2+. The Ca2+ binding protein calmodulin confers sub-micromolar Ca2+ sensitivity to the channel-calmodulin complex. The calmodulin C-lobe is constitutively associated with the proximal C-terminus of the channel. Interactions between calmodulin N-lobe and the channel S4-S5 linker are Ca2+-dependent, which subsequently trigger conformational changes in the channel pore and open the gate. KCNN genes encode four subtypes, including KCNN1 for KCa2.1 (SK1), KCNN2 for KCa2.2 (SK2), KCNN3 for KCa2.3 (SK3), and KCNN4 for KCa3.1 (IK). The three KCa2.x channel subtypes are expressed in the central nervous system and the heart. The KCa3.1 subtype is expressed in the erythrocytes and the lymphocytes, among other peripheral tissues. The impact of dysfunctional KCa2.x/KCa3.1 channels on human health has not been well documented. Human loss-of-function KCa2.2 mutations have been linked with neurodevelopmental disorders. Human gain-of-function mutations that increase the apparent Ca2+ sensitivity of KCa2.3 and KCa3.1 channels have been associated with Zimmermann-Laband syndrome and hereditary xerocytosis, respectively. This review article discusses the physiological significance of KCa2.x/KCa3.1 channels, the pathophysiology of the diseases linked with KCa2.x/KCa3.1 mutations, the structure–function relationship of the mutant KCa2.x/KCa3.1 channels, and potential pharmacological therapeutics for the KCa2.x/KCa3.1 channelopathy.

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Fig. 1: KCa2.2 channel structure and LOF mutations.
Fig. 2: KCa2.3 channel structure and GOF mutations.
Fig. 3: KCa3.1 channel structure and GOF mutations.

References

  1. Aldrich RW, Chandy KG, Grissmer S, Gutman GA, Kaczmarek LK, Wei AD, et al. Calcium- and sodium-activated potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database. IUPHAR/BPS Guide to Pharmacology CITE. 2019.

  2. Xia XM, Fakler B, Rivard A, Wayman G, Johnson-Pais T, Keen JE, et al. Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature. 1998;395:503–7.

    Article  CAS  Google Scholar 

  3. Brown BM, Shim H, Christophersen P, Wulff H. Pharmacology of small- and intermediate-conductance calcium-activated potassium channels. Annu Rev Pharmacol Toxicol. 2020;60:219–40.

    Article  CAS  Google Scholar 

  4. Higham J, Sahu G, Wazen RM, Colarusso P, Gregorie A, Harvey BSJ, et al. Preferred formation of heteromeric channels between coexpressed SK1 and IKCa Channel subunits provides a unique pharmacological profile of Ca2+-activated potassium channels. Mol Pharmacol. 2019;96:115–26.

    Article  CAS  Google Scholar 

  5. Tuteja D, Rafizadeh S, Timofeyev V, Wang S, Zhang Z, Li N, et al. Cardiac small conductance Ca2+-activated K+ channel subunits form heteromultimers via the coiled-coil domains in the C termini of the channels. Circ Res. 2010;107:851–9.

    Article  CAS  Google Scholar 

  6. Kohler M, Hirschberg B, Bond CT, Kinzie JM, Marrion NV, Maylie J, et al. Small-conductance, calcium-activated potassium channels from mammalian brain. Science. 1996;273:1709–14.

    Article  CAS  Google Scholar 

  7. Ishii TM, Silvia C, Hirschberg B, Bond CT, Adelman JP, Maylie J. A human intermediate conductance calcium-activated potassium channel. Proc Natl Acad Sci USA. 1997;94:11651–6.

    Article  CAS  Google Scholar 

  8. Lee CH, MacKinnon R. Activation mechanism of a human SK-calmodulin channel complex elucidated by cryo-EM structures. Science. 2018;360:508–13.

    Article  CAS  Google Scholar 

  9. Adelman JP, Maylie J, Sah P. Small-conductance Ca2+-activated K+ channels: form and function. Annu Rev Physiol. 2012;74:245–69.

    Article  CAS  Google Scholar 

  10. Pedarzani P, McCutcheon JE, Rogge G, Jensen BS, Christophersen P, Hougaard C, et al. Specific enhancement of SK channel activity selectively potentiates the afterhyperpolarizing current IAHP and modulates the firing properties of hippocampal pyramidal neurons. J Biol Chem. 2005;280:41404–11.

    Article  CAS  Google Scholar 

  11. Pedarzani P, Stocker M. Molecular and cellular basis of small- and intermediate-conductance, calcium-activated potassium channel function in the brain. Cell Mol Life Sci. 2008;65:3196–217.

    Article  CAS  Google Scholar 

  12. Giessel AJ, Sabatini BL. M1 muscarinic receptors boost synaptic potentials and calcium influx in dendritic spines by inhibiting postsynaptic SK channels. Neuron. 2010;68:936–47.

    Article  CAS  Google Scholar 

  13. Buchanan KA, Petrovic MM, Chamberlain SE, Marrion NV, Mellor JR. Facilitation of long-term potentiation by muscarinic M(1) receptors is mediated by inhibition of SK channels. Neuron. 2010;68:948–63.

    Article  CAS  Google Scholar 

  14. Womack MD, Khodakhah K. Somatic and dendritic small-conductance calcium-activated potassium channels regulate the output of cerebellar Purkinje neurons. J Neurosci. 2003;23:2600–7.

    Article  CAS  Google Scholar 

  15. Cingolani LA, Gymnopoulos M, Boccaccio A, Stocker M, Pedarzani P. Developmental regulation of small-conductance Ca2+-activated K+ channel expression and function in rat Purkinje neurons. J Neurosci. 2002;22:4456–67.

    Article  CAS  Google Scholar 

  16. Hosy E, Piochon C, Teuling E, Rinaldo L, Hansel C. SK2 channel expression and function in cerebellar Purkinje cells. J Physiol. 2011;589:3433–40.

    Article  CAS  Google Scholar 

  17. Sailer CA, Kaufmann WA, Marksteiner J, Knaus HG. Comparative immunohistochemical distribution of three small-conductance Ca2+-activated potassium channel subunits, SK1, SK2, and SK3 in mouse brain. Mol Cell Neurosci. 2004;26:458–69.

    Article  CAS  Google Scholar 

  18. Kuramoto T, Yokoe M, Kunisawa N, Ohashi K, Miyake T, Higuchi Y, et al. Tremor dominant Kyoto (Trdk) rats carry a missense mutation in the gene encoding the SK2 subunit of small-conductance Ca2+-activated K+ channel. Brain Res. 2017;1676:38–45.

    Article  CAS  Google Scholar 

  19. Mochel F, Rastetter A, Ceulemans B, Platzer K, Yang S, Shinde DN, et al. Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders. Brain. 2020;143:3564–73.

    Article  Google Scholar 

  20. Egorova PA, Bezprozvanny IB. Electrophysiological studies support utility of positive modulators of SK channels for treatment of spinocerebellar ataxia type 2. Cerebellum. Epub 2022 Jan 3. https://doi.org/10.1007/s12311-021-01349-1.

  21. Xu Y, Tuteja D, Zhang Z, Xu D, Zhang Y, Rodriguez J, et al. Molecular identification and functional roles of a Ca2+-activated K+ channel in human and mouse hearts. J Biol Chem. 2003;278:49085–94.

    Article  CAS  Google Scholar 

  22. Tuteja D, Xu D, Timofeyev V, Lu L, Sharma D, Zhang Z, et al. 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. 2005;289:H2714–23.

    Article  CAS  Google Scholar 

  23. Zhang Q, Timofeyev V, Lu L, Li N, Singapuri A, Long MK, et al. Functional roles of a Ca2+-activated K+ channel in atrioventricular nodes. Circ Res. 2008;102:465–71.

    Article  CAS  Google Scholar 

  24. Yu CC, Chia-Ti T, Chen PL, Wu CK, Chiu FC, Chiang FT, et al. KCNN2 polymorphisms and cardiac tachyarrhythmias. Medicines. 2016;95:e4312.

    CAS  Google Scholar 

  25. Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, Chung MK, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010;42:240–4.

    Article  CAS  Google Scholar 

  26. Zhang XD, Thai PN, Lieu DK, Chiamvimonvat N. Cardiac small-conductance calcium-activated potassium channels in health and disease. Pflug Arch: Eur J Physiol. 2021;473:477–89.

    Article  CAS  Google Scholar 

  27. Wulff H, Kohler R. Endothelial small-conductance and intermediate-conductance KCa channels: an update on their pharmacology and usefulness as cardiovascular targets. J Cardiovasc Pharmacol. 2013;61:102–12.

    Article  CAS  Google Scholar 

  28. Brahler S, Kaistha A, Schmidt VJ, Wolfle SE, Busch C, Kaistha BP, et al. Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension. Circulation. 2009;119:2323–32.

    Article  Google Scholar 

  29. Feletou M. Endothelium-dependent hyperpolarization and endothelial dysfunction. J Cardiovasc Pharmacol. 2016;67:373–87.

    Article  CAS  Google Scholar 

  30. Hoffman JF, Joiner W, Nehrke K, Potapova O, Foye K, Wickrema A. The hSK4 (KCNN4) isoform is the Ca2+-activated K+ channel (Gardos channel) in human red blood cells. Proc Natl Acad Sci USA. 2003;100:7366–71.

    Article  CAS  Google Scholar 

  31. Logsdon NJ, Kang J, Togo JA, Christian EP, Aiyar J. A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes. J Biol Chem. 1997;272:32723–6.

    Article  CAS  Google Scholar 

  32. Jensen BS, Odum N, Jorgensen NK, Christophersen P, Olesen SP. Inhibition of T cell proliferation by selective block of Ca2+-activated K+ channels. Proc Natl Acad Sci USA. 1999;96:10917–21.

    Article  CAS  Google Scholar 

  33. Rapetti-Mauss R, Picard V, Guitton C, Ghazal K, Proulle V, Badens C, et al. Red blood cell Gardos channel (KCNN4): the essential determinant of erythrocyte dehydration in hereditary xerocytosis. Haematologica. 2017;102:e415–e8.

    Article  CAS  Google Scholar 

  34. Balint B, Guerreiro R, Carmona S, Dehghani N, Latorre A, Cordivari C, et al. KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia. Eur J Neurol. 2020;27:1471–7.

    Article  CAS  Google Scholar 

  35. Bauer CK, Schneeberger PE, Kortum F, Altmuller J, Santos-Simarro F, Baker L, et al. Gain-of-function mutations in KCNN3 encoding the small-conductance Ca2+-activated K+ channel SK3 cause Zimmermann-Laband syndrome. Am J Hum Genet. 2019;104:1139–57.

    Article  CAS  Google Scholar 

  36. Gripp KW, Smithson SF, Scurr IJ, Baptista J, Majumdar A, Pierre G, et al. Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K+ channelopathies. Eur J Hum Genet. 2021;29:1384–95.

    Article  CAS  Google Scholar 

  37. Schwarz M, Ryba L, Krepelova A, Moslerova V, Zelinova M, Turnovec M, et al. Zimmermann-Laband syndrome in monozygotic twins with a mild neurobehavioral phenotype lacking gingival overgrowth-A case report of a novel KCNN3 gene variant. Am J Med Genet A. 2022;188:1083–7.

  38. Koot BG, Alders M, Verheij J, Beuers U, Cobben JM. A de novo mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension. J Hepatol. 2016;64:974–7.

    Article  CAS  Google Scholar 

  39. Fermo E, Bogdanova A, Petkova-Kirova P, Zaninoni A, Marcello AP, Makhro A, et al. ‘Gardos Channelopathy’: a variant of hereditary Stomatocytosis with complex molecular regulation. Sci Rep. 2017;7:1744.

    Article  Google Scholar 

  40. Fermo E, Monedero-Alonso D, Petkova-Kirova P, Makhro A, Peres L, Bouyer G, et al. Gardos channelopathy: functional analysis of a novel KCNN4 variant. Blood Adv. 2020;4:6336–41.

    Article  CAS  Google Scholar 

  41. Mansour-Hendili L, Egee S, Monedero-Alonso D, Bouyer G, Godeau B, Badaoui B, et al. Multiple thrombosis in a patient with Gardos channelopathy and a new KCNN4 mutation. Am J Hematol. 2021;96:E318–21.

  42. Picard V, Guitton C, Thuret I, Rose C, Bendelac L, Ghazal K, et al. Clinical and biological features in PIEZO1-hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients. Haematologica. 2019;104:1554–64.

    Article  CAS  Google Scholar 

  43. Rapetti-Mauss R, Lacoste C, Picard V, Guitton C, Lombard E, Loosveld M, et al. A mutation in the Gardos channel is associated with hereditary xerocytosis. Blood. 2015;126:1273–80.

    Article  CAS  Google Scholar 

  44. Szatanik M, Vibert N, Vassias I, Guénet J-L, Eugène D, de Waele C, et al. Behavioral effects of a deletion in Kcnn2, the gene encoding the SK2 subunit of small-conductance Ca2+-activated K+ channels. Neurogenetics. 2008;9:237–48.

    Article  CAS  Google Scholar 

  45. Walter JT, Alvina K, Womack MD, Chevez C, Khodakhah K. Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci. 2006;9:389–97.

    Article  CAS  Google Scholar 

  46. Hoebeek FE, Stahl JS, van Alphen AM, Schonewille M, Luo C, Rutteman M, et al. Increased noise level of purkinje cell activities minimizes impact of their modulation during sensorimotor control. Neuron. 2005;45:953–65.

    Article  CAS  Google Scholar 

  47. Dell’Orco JM, Wasserman AH, Chopra R, Ingram MA, Hu YS, Singh V, et al. Neuronal atrophy early in degenerative ataxia is a compensatory mechanism to regulate membrane excitability. J Neurosci. 2015;35:11292–307.

    Article  Google Scholar 

  48. Hansen ST, Meera P, Otis TS, Pulst SM. Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2. Hum Mol Genet. 2013;22:271–83.

    Article  CAS  Google Scholar 

  49. Shakkottai VG, do Carmo Costa M, Dell’Orco JM, Sankaranarayanan A, Wulff H, Paulson HL. Early changes in cerebellar physiology accompany motor dysfunction in the polyglutamine disease spinocerebellar ataxia type 3. J Neurosci. 2011;31:13002–14.

    Article  CAS  Google Scholar 

  50. Mark MD, Krause M, Boele HJ, Kruse W, Pollok S, Kuner T, et al. Spinocerebellar ataxia type 6 protein aggregates cause deficits in motor learning and cerebellar plasticity. J Neurosci. 2015;35:8882–95.

    Article  CAS  Google Scholar 

  51. Dougherty SE, Reeves JL, Lucas EK, Gamble KL, Lesort M, Cowell RM. Disruption of Purkinje cell function prior to huntingtin accumulation and cell loss in an animal model of Huntington disease. Exp Neurol. 2012;236:171–8.

    Article  CAS  Google Scholar 

  52. Dougherty SE, Reeves JL, Lesort M, Detloff PJ, Cowell RM. Purkinje cell dysfunction and loss in a knock-in mouse model of Huntington disease. Exp Neurol. 2013;240:96–102.

    Article  CAS  Google Scholar 

  53. Egorova PA, Gavrilova AV, Bezprozvanny IB. Ataxic symptoms in Huntington’s disease transgenic mouse model are alleviated by chlorzoxazone. Front Neurosci. 2020;14:279.

    Article  Google Scholar 

  54. Meera P, Pulst SM, Otis TS. Cellular and circuit mechanisms underlying spinocerebellar ataxias. J Physiol. 2016;594:4653–60.

    Article  CAS  Google Scholar 

  55. Hammond RS, Bond CT, Strassmaier T, Ngo-Anh TJ, Adelman JP, Maylie J, et al. Small-conductance Ca2+-activated K+ channel type 2 (SK2) modulates hippocampal learning, memory, and synaptic plasticity. J Neurosci. 2006;26:1844–53.

    Article  CAS  Google Scholar 

  56. Alonso-Gonzalez A, Calaza M, Rodriguez-Fontenla C, Carracedo A. Novel gene-based analysis of ASD GWAS: insight into the biological role of associated genes. Front Genet. 2019;10:733.

    Article  CAS  Google Scholar 

  57. Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H, et al. Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019;51:431–44.

    Article  CAS  Google Scholar 

  58. Garcia-Junco-Clemente P, Chow DK, Tring E, Lazaro MT, Trachtenberg JT, Golshani P. Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism. Proc Natl Acad Sci USA. 2013;110:18297–302.

    Article  CAS  Google Scholar 

  59. Kortum F, Caputo V, Bauer CK, Stella L, Ciolfi A, Alawi M, et al. Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nat Genet. 2015;47:661–7.

    Article  Google Scholar 

  60. Bauer CK, Calligari P, Radio FC, Caputo V, Dentici ML, Falah N, et al. Mutations in KCNK4 that affect gating cause a recognizable neurodevelopmental syndrome. Am J Hum Genet. 2018;103:621–30.

    Article  CAS  Google Scholar 

  61. Orfali R, Nam YW, Nguyen HM, Rahman MA, Yang G, Cui M, et al. Channelopathy-causing mutations in the S45A/S45B and HA/HB helices of KCa2.3 and KCa3.1 channels alter their apparent Ca2+ sensitivity. Cell Calcium. 2022;102:102538.

    Article  CAS  Google Scholar 

  62. Raffetto JD, Yu P, Reslan OM, Xia Y, Khalil RA. Endothelium-dependent nitric oxide and hyperpolarization-mediated venous relaxation pathways in rat inferior vena cava. J Vasc Surg. 2012;55:1716–25.

    Article  Google Scholar 

  63. Freise C, Heldwein S, Erben U, Hoyer J, Kohler R, Johrens K, et al. K+-channel inhibition reduces portal perfusion pressure in fibrotic rats and fibrosis associated characteristics of hepatic stellate cells. Liver Int. 2015;35:1244–52.

    Article  CAS  Google Scholar 

  64. Martin S, Lazzarini M, Dullin C, Balakrishnan S, Gomes FV, Ninkovic M, et al. SK3 channel overexpression in mice causes hippocampal shrinkage associated with cognitive impairments. Mol Neurobiol. 2017;54:1078–91.

    Article  CAS  Google Scholar 

  65. Tommiska J, Kansakoski J, Skibsbye L, Vaaralahti K, Liu X, Lodge EJ, et al. Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis. Nat Commun. 2017;8:1289.

    Article  Google Scholar 

  66. Brownstein CA, Towne MC, Luquette LJ, Harris DJ, Marinakis NS, Meinecke P, et al. Mutation of KCNJ8 in a patient with Cantu syndrome with unique vascular abnormalities - support for the role of KATP channels in this condition. Eur J Med Genet. 2013;56:678–82.

    Article  Google Scholar 

  67. Gao Q, Yang C, Meng L, Wang Z, Chen D, Peng Y, et al. Activated KCNQ1 channel promotes fibrogenic response in hereditary gingival fibromatosis via clustering and activation of Ras. J Periodontal Res. 2021;56:471–81.

    Article  CAS  Google Scholar 

  68. Jankovsky N, Caulier A, Demagny J, Guitton C, Djordjevic S, Lebon D, et al. Recent advances in the pathophysiology of PIEZO1-related hereditary xerocytosis. Am J Hematol. 2021;96:1017–26.

    Article  CAS  Google Scholar 

  69. Glogowska E, Lezon-Geyda K, Maksimova Y, Schulz VP, Gallagher PG. Mutations in the Gardos channel (KCNN4) are associated with hereditary xerocytosis. Blood. 2015;126:1281–4.

    Article  CAS  Google Scholar 

  70. Andolfo I, Russo R, Manna F, Shmukler BE, Gambale A, Vitiello G, et al. Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis). Am J Hematol. 2015;90:921–6.

    Article  CAS  Google Scholar 

  71. Kaestner L, Bogdanova A, Egee S. Calcium channels and calcium-regulated channels in human red blood cells. Adv Exp Med Biol. 2020;1131:625–48.

    Article  CAS  Google Scholar 

  72. Nam YW, Cui M, Orfali R, Viegas A, Nguyen M, Mohammed EHM, et al. Hydrophobic interactions between the HA helix and S4-S5 linker modulate apparent Ca2+ sensitivity of SK2 channels. Acta Physiol. 2021;231:e13552.

    Article  CAS  Google Scholar 

  73. Crivici A, Ikura M. Molecular and structural basis of target recognition by calmodulin. Annu Rev Biophysics Biomol Struct. 1995;24:85–116.

    Article  CAS  Google Scholar 

  74. Shim H, Brown BM, Singh L, Singh V, Fettinger JC, Yarov-Yarovoy V, et al. The trials and tribulations of structure assisted design of KCa channel activators. Front Pharmacol. 2019;10:972.

    Article  CAS  Google Scholar 

  75. Dart C, Leyland ML, Spencer PJ, Stanfield PR, Sutcliffe MJ. The selectivity filter of a potassium channel, murine kir2.1, investigated using scanning cysteine mutagenesis. J Physiol. 1998;511(Pt 1):25–32.

    Article  CAS  Google Scholar 

  76. Garneau L, Klein H, Banderali U, Longpre-Lauzon A, Parent L, Sauve R. Hydrophobic interactions as key determinants to the KCa3.1 channel closed configuration. An analysis of KCa3.1 mutants constitutively active in zero Ca2+. J Biol Chem. 2009;284:389–403.

    Article  Google Scholar 

  77. Allen D, Fakler B, Maylie J, Adelman JP. Organization and regulation of small conductance Ca2+-activated K+ channel multiprotein complexes. J Neurosci. 2007;27:2369–76.

    Article  CAS  Google Scholar 

  78. Islas LD. Functional diversity of potassium channel voltage-sensing domains. Channels. 2016;10:202–13.

    Article  Google Scholar 

  79. Ishii TM, Maylie J, Adelman JP. Determinants of apamin and d-tubocurarine block in SK potassium channels. J Biol Chem. 1997;272:23195–200.

    Article  CAS  Google Scholar 

  80. Benton DC, Monaghan AS, Hosseini R, Bahia PK, Haylett DG, Moss GW. Small conductance Ca2+-activated K+ channels formed by the expression of rat SK1 and SK2 genes in HEK 293 cells. J Physiol. 2003;553:13–9.

    Article  CAS  Google Scholar 

  81. Monaghan AS, Benton DCH, Bahia PK, Hosseini R, Shah YA, Haylett DG, et al. The SK3 subunit of small conductance Ca2+-activated K+ channels interacts with both SK1 and SK2 subunits in a heterologous expression system. J Biol Chem. 2004;279:1003–9.

    Article  CAS  Google Scholar 

  82. Fanger CM, Rauer H, Neben AL, Miller MJ, Rauer H, Wulff H, et al. Calcium-activated potassium channels sustain calcium signaling in T lymphocytes. Selective blockers and manipulated channel expression levels. J Biol Chem. 2001;276:12249–56.

    Article  CAS  Google Scholar 

  83. Shakkottai VG, Chou CH, Oddo S, Sailer CA, Knaus HG, Gutman GA, et al. Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. J Clin Invest. 2004;113:582–90.

    Article  CAS  Google Scholar 

  84. Tomita H, Shakkottai VG, Gutman GA, Sun G, Bunney WE, Cahalan MD, et al. Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia. Mol Psychiatr. 2003;8:524–35.

    Article  CAS  Google Scholar 

  85. Bulaklak K, Gersbach CA. The once and future gene therapy. Nat Commun. 2020;11:5820.

    Article  CAS  Google Scholar 

  86. Stocker JW, De Franceschi L, McNaughton-Smith GA, Corrocher R, Beuzard Y, Brugnara C. ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. Blood. 2003;101:2412–8.

    Article  CAS  Google Scholar 

  87. Rapetti-Mauss R, Soriani O, Vinti H, Badens C, Guizouarn H. Senicapoc: a potent candidate for the treatment of a subset of hereditary xerocytosis caused by mutations in the Gardos channel. Haematologica. 2016;101:e431–e5.

    Article  Google Scholar 

  88. Simo-Vicens R, Kirchhoff JE, Dolce B, Abildgaard L, Speerschneider T, Sorensen US, et al. A new negative allosteric modulator, AP14145, for the study of small conductance calcium-activated potassium (KCa 2) channels. Br J Pharmacol. 2017;174:4396–408.

    Article  CAS  Google Scholar 

  89. Hougaard C, Eriksen BL, Jorgensen S, Johansen TH, Dyhring T, Madsen LS, et al. Selective positive modulation of the SK3 and SK2 subtypes of small conductance Ca2+-activated K+ channels. Br J Pharmacol. 2007;151:655–65.

    Article  CAS  Google Scholar 

  90. Nam YW, Cui M, El-Sayed NS, Orfali R, Nguyen M, Yang G, et al. Subtype-selective positive modulation of KCa 2 channels depends on the HA/HB helices. Br J Pharmacol. 2022;179:460–72.

    Article  CAS  Google Scholar 

  91. El-Sayed NS, Nam YW, Egorova PA, Nguyen HM, Orfali R, Rahman MA, et al. Structure-activity relationship study of subtype-selective positive modulators of KCa2 channels. J Med Chem. 2022;65:303–22.

    Article  CAS  Google Scholar 

  92. Jin LW, Lucente JD, Nguyen HM, Singh V, Singh L, Chavez M, et al. Repurposing the KCa3.1 inhibitor senicapoc for Alzheimer’s disease. Ann Clin Transl Neurol. 2019;6:723–38.

    Article  CAS  Google Scholar 

  93. Wulff H, Gutman GA, Cahalan MD, Chandy KG. Delineation of the clotrimazole/TRAM-34 binding site on the intermediate conductance calcium-activated potassium channel, IKCa1. J Biol Chem. 2001;276:32040–5.

    Article  CAS  Google Scholar 

  94. Wulff H, Miller MJ, Hansel W, Grissmer S, Cahalan MD, Chandy KG. Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proc Natl Acad Sci USA. 2000;97:8151–6.

    Article  CAS  Google Scholar 

  95. Coleman N, Brown BM, Olivan-Viguera A, Singh V, Olmstead MM, Valero MS, et al. New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1. Mol Pharmacol. 2014;86:342–57.

    Article  Google Scholar 

  96. Strobaek D, Hougaard C, Johansen TH, Sorensen US, Nielsen EO, Nielsen KS, et al. 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. 2006;70:1771–82.

    Article  Google Scholar 

  97. Kasumu AW, Hougaard C, Rode F, Jacobsen TA, Sabatier JM, Eriksen BL, et al. Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2. Chem Biol. 2012;19:1340–53.

    Article  CAS  Google Scholar 

  98. Olivan-Viguera A, Valero MS, Coleman N, Brown BM, Laria C, Murillo MD, et al. A novel pan-negative-gating modulator of KCa2/3 channels, fluoro-di-benzoate, RA-2, inhibits endothelium-derived hyperpolarization-type relaxation in coronary artery and produces bradycardia in vivo. Mol Pharmacol. 2015;87:338–48.

    Article  Google Scholar 

  99. Strobaek D, Teuber L, Jorgensen TD, Ahring PK, Kjaer K, Hansen RS, et al. 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. 2004;1665:1–5.

    Article  CAS  Google Scholar 

  100. Sankaranarayanan A, Raman G, Busch C, Schultz T, Zimin PI, Hoyer J, et al. 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. 2009;75:281–95.

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to Lucia Basilio, Young Hur, Misa Nguyen, Nadeed Naguib, Elyn Lam, and Nikita Dave for their helpful suggestions. M.Z. was supported by a Scientist Development Grant 13SDG16150007 from American Heart Association, a YI-SCA grant from National Ataxia Foundation, and a grant 4R33NS101182-03 from NIH.

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Authors and Affiliations

  1. Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, 92618, USA

    Young-Woo Nam, Myles Downey, Mohammad Asikur Rahman & Miao Zhang

  2. Department of Pharmaceutical Sciences, Northeastern University School of Pharmacy, Boston, MA, 02115, USA

    Meng Cui

Authors
  1. Young-Woo Nam
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  2. Myles Downey
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  3. Mohammad Asikur Rahman
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  4. Meng Cui
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  5. Miao Zhang
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Contributions

M.C. and M.Z. conceptualized the project. All authors contributed to the manuscript and the figures.

Corresponding author

Correspondence to Miao Zhang.

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The authors declare no competing interests.

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Nam, YW., Downey, M., Rahman, M.A. et al. Channelopathy of small- and intermediate-conductance Ca2+-activated K+ channels. Acta Pharmacol Sin 44, 259–267 (2023). https://doi.org/10.1038/s41401-022-00935-1

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  • DOI: https://doi.org/10.1038/s41401-022-00935-1

Keywords

  • channelopathy
  • KCa2.2 channels
  • KCa2.3 channels
  • KCa3.1 channels
  • Zimmermann-Laband syndrome
  • hereditary xerocytosis

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