TABLE 6

KCa3.1 channels

Channel name KCa3.1
Description Intermediate-conductance, calcium-activated potassium channel; activated via a calmodulin-dependent mechanism
Other names SK41,1 IK1,2 Gardos channel, KCa4,3 IKCa14
Molecular information Human: 427aa, NM_002250, chr. 19q13.2,4,5 KCNN4
Mouse: 425aa, NM_008433, chr. 7
Rat: 424aa, NM_023021, 1q21
Associated subunits Calmodulin tightly complexed to C terminus6
Functional assays Electrophysiology
Current Gardos channel in erythrocytes,7 IK current in lymphocytes,8 fibroblasts9
Conductance 11pS1,2,3,8
Ion selectivity K+ (1) > Rb+ (0.96) > NH4+ (0.17) > Cs+ (0.07)8
Activation Activated by intracellular Ca2+ (Kd = 0.1–0.3 μM; nH = 1.7–4)1,2,3,4,8
Inactivation None
Activators EBIO, NS309 (10 nM),10 DCEBIO (1 μM),11 riluzole (1 μM), methylxanthine (theophylline, caffeine, IBMX)12
Gating inhibitors None
Blockers ChTX (5 nM),1,2,3,4,14,15 maurotoxin (1 nM),15 4-phenyl-4H-pyran 11 (8 nM),16 ICA17043 (11 nM),17 TRAM-34 (20 nM),14,15 ChTX-Glu13,32 (33 nM),14,15 ShK (30 nM),14 clotrimazole (70 nM),14,15 BgK (172 nM),14 TRAM-3 (520 nM),15 nitredipine (900 nM), nimodipine (1 μM), and nifedipine (4 μM),14 UCL1608 (4 μM),18 ketoconazole (30 μM) and econazole (12 μM),14,15 cetiedil,18 TEA (24 mM)14
Radioligands None
Channel distribution Placenta, prostate, erythrocytes,19 lymphocytes,3,4 microglia, liver, foetal liver, pancreas, hematopoietic stem cells, fibroblasts,9 HL60, colon, Paneth cells,20 melanomas,21 proliferating smooth muscle cells,22 vascular endothelium,23 lung and colonic endothelium
Physiological functions KCa3.1 is involved in volume regulation in erythrocytes19,24; its expression is up-regulated during activation of lymphocytes, and specific blockers suppress lymphocyte4,8,25,26 and vascular smooth muscle cell proliferation22; KCa3.1 is involved in EDHF-mediated vasodilatation23 and in angiogenesis27,28
Mutations and pathophysiology T lymphocytes and erythrocytes from KCa3.1 knockout mouse show sever defect in volume regulation29
Pharmacological significance KCa3.1 blocker ICA17043 is in clinical trials for sickle cell anemia24; KCa3.1 blockers are of potential use for the treatment of diarrhea30 and as immunosuppressants14,31; TRAM-34 has been shown to treat EAE in mice32 and prevent restenosis in rats22 and angiogenesis in mice28; KCa3.1 blockers reduce experimental brain oedema and attenuate traumatic brain injury33; KCa3.1 openers are considered as potential therapeutics for cystic fibrosis and chronic obstructive pulmonary disease11
Comments Voltage-independent calmodulin is also involved in trafficking34; intron-exon structure shared with KCa2.1–KCa2.3 (SK channels)

  • aa, amino acids; chr., chromosome; NS309, 6,7-dichloro-1H-indole-2,3-dione-3-oxime; IK, intermediate-conductance K+ channel; EBIO, 1-ethyl-2-benzimidazolinone; DCEBIO, 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one; ChTX, charybdotoxin; ShK, ShK toxin, a potassium channel blocker from the sea anemone Stichodactyla helianthus; BgK, BgK toxin, a potassium channel blocker from the sea anemone Bunodosoma granulifera; EAE, experimental autoimmune encephalomyelitis; SK, small-conductance K+ channel; ICA17043, bis(4-fluorophenyl)phenyl acetamide; UCL1608, 1-[(9-benzyl)fluoren-9-yl]-4-(hexahydro-1H-azepin-1-yl)but-2-yne hydrogen oxalate; IBMX, 3-isobutyl-1-methylxanthine; TEA, tetraethylammonium; EDHF, endothelium-derived hyperpolarizing factor.

  • ↵1. Joiner WJ, Wang LY, Tang MD, and Kaczmarek LK (1997) hSK4, a member of a novel subfamily of calcium-activated potassium channels. Proc Natl Acad Sci USA 94:11013-11018

  • ↵2. Ishii TM, Silvia C, Hirschberg B, Bond CT, Adelman JP, and Maylie J (1997) A human intermediate conductance calcium-activated potassium channel. Proc Natl Acad Sci USA 94:11651-11656

  • ↵3. Logsdon NJ, Kang J, Togo JA, Christian EP, and Aiyar J (1997) A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes. J Biol Chem 272:32723-32726

  • ↵4. 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

  • ↵5. Ghanshani S, Coleman M, Gustavsson P, Wu AC, Gargus JJ, Gutman GA, Dahl N, Mohrenweiser H, and Chandy KG (1998) Human calcium-activated potassium channel gene KCNN4 maps to chromosome 19q13.2 in the region deleted in diamond-black fan anemia. Genomics 51:160-161

  • ↵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. Gardos G (1958) The function of calcium in the potassium permeability of human erythrocytes. Biochim Biophys Acta 30:653-654

  • ↵8. Grissmer S, Nguyen AN, and Cahalan MD (1993) Calcium-activated potassium channels in resting and activated human T lymphocytes. Expression levels, calcium dependence, ion selectivity, and pharmacology. J Gen Physiol 102:601-630

  • ↵9. Pena TL, Chen SH, Konieczny SF, and Rane SG (2000) Ras/MEK/ERK up-regulation of the fibroblast KCa channel FIK is a common mechanism for basic fibroblast growth factor and transforming growth factor-beta suppression of myogenesis. J Biol Chem 275:13677-13682

  • ↵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. Singh S, Syme CA, Singh AK, Devor DC, and Bridges RJ (2001) Benzimidazolone activators of chloride secretion: potential therapeutics for cystic fibrosis and chronic obstructive pulmonary disease. J Pharmacol Exp Ther 296:600-611

  • ↵12. Schroder RL, Jensen BS, Strobaek D, Olesen SP, and Christophersen P (2000) Activation of the human, intermediate-conductance, Ca2+-activated K+ channel by methylxanthines. Pflugers Arch Eur J Physiol 440:809-818

  • ↵13. Rauer H, Lanigan MD, Pennington MW, Aiyar J, Ghanshani S, Cahalan MD, Norton RS, and Chandy KG (2000) Structure-guided transformation of charybdotoxin yields an analog that selectively targets Ca2+-activated over voltage-gated K+ channels. J Biol Chem 275:1201-1208

  • ↵14. Chandy KG, Wulff H, Beeton C, Pennington M, Gutman GA, and Cahalan MD (2004) K+ channels as targets for specific immunomodulation. Trends Pharmacol Sci 25:280-289

  • ↵15. Wulff H, Miller MJ, Haensel W, Grissmer S, Cahalan MD, and Chandy KG (2000) Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proc Natl Acad Sci USA 97:8151-8156

  • ↵16. Urbahns K, Horvath E, Stasch JP, and Mauler F (2003) 4-Phenyl-4H-pyrans as IK (Ca) channel blockers. Bioorg Med Chem Lett 13:2637-2639

  • ↵17. Stocker JW, De Franceschi L, McNaughton-Smith GA, Corrocher R, Beuzard Y, and Brugnara C (2003) ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. Blood 101:2412-2418

  • ↵18. Roxburgh CJ, Ganellin CR, Athmani S, Bisi A, Quaglia W, Benton DC, Shiner MA, Malik-Hall M, Haylett DG, and Jenkinson DH (2001) Synthesis and structure-activity relationships of cetiedil analogues as blockers of the Ca2+-activated K+ permeability of erythrocytes. J Med Chem 44:3244-3253

  • ↵19. Vandorpe DH, Shmukler BE, Jiang L, Lim B, Maylie J, Adelman JP, de Franceschi L, Cappellini MD, Brugnara C, and Alper SL (1998) cDNA cloning and functional characterization of the mouse Ca2+-gated K+ channel, mIK1Roles in regulatory volume decrease and erythroid differentiation. J Biol Chem 273:21542-21553

  • ↵20. Ayabe T, Wulff H, Darmoul D, Cahalan MD, Chandy KG, and Ouellette AJ (2002) Modulation of mouse Paneth cell alpha-defensin secretion by mIKCa1, a Ca2+- activated, intermediate conductance potassium channel. J Biol Chem 277:3793-3800

  • ↵21. Meyer R, Schonherr R, Gavrilova-Ruch O, Wohlrab W, and Heinemann SH (1999) Identification of ether a go-go and calcium-activated potassium channels in human melanoma cells. J Membr Biol 171:107-115

  • ↵22. Kohler R, Wulff H, Eichler I, Kneifel M, Neumann D, Knorr A, Grgic I, Kampfe D, Si H, Wibawa J, et al. (2003) Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis Circulation 108:1119-1125

  • ↵23. Eichler I, Wibawa J, Grgic I, Knorr A, Brakemeier S, Pries AR, Hoyer J, and Kohler R (2003) Selective blockade of endothelial Ca2+-activated small- and intermediate-conductance K+-channels suppresses EDHF-mediated vasodilation. Br J Pharmacol 138:594-601

  • ↵24. Brugnara C, Gee B, Armsby CC, Kurth S, Sakamoto M, Rifai N, Alper SL, and Platt OS (1996) Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease. J Clin Investig 97:1227-1234

  • ↵25. Jensen BS, Odum N, Jorgensen NK, Christophersen P, and Olesen SP (1999) Inhibition of T cell proliferation by selective block of Ca (2+)-activated K (+) channels. Proc Natl Acad Sci USA 96:10917-10921

  • ↵26. Khanna R, Chang MC, Joiner WJ, Kaczmarek LK, and Schlichter LC (1999) hSK4/hIK1, a calmodulin-binding KCa channel in human T lymphocytes. Roles in proliferation and volume regulation. J Biol Chem 274:14838-14849

  • ↵27. Kohler R, Degenhardt C, Kuhn M, Runkel N, Paul M, and Hoyer J (2000) Expression and function of endothelial Ca2+-activated K+ channels inhuman mesenteric artery: a single-cell reverse transcriptase-polymerase chain reaction and electrophysiological study in situ. Circ Res 87:496-503

  • ↵28. Grgic I, Eichler I, Heinau P, Si H, Brakemeier S, Hoyer J, and Kohler R (2005) Selective blockade of the intermediate-conductance Ca2+-activated K+ channel suppresses proliferation of microvascular and macrovascular endothelial cells and angiogenesis in vivo. Arterioscler Thromb Vasc Biol 25:704-709

  • ↵29. Begenisich T, Nakamoto T, Ovitt CE, Nehrke K, Brugnara C, Alper SL, and Melvin JE (2004) Physiological roles of the intermediate conductance, Ca2+-activatedpotassium channel Kcnn4. J Biol Chem 279:47681-47687

  • ↵30. Rufo PA, Merlin D, Riegler M, Ferguson-Maltzman MH, Dickinson BL, Brugnara C, Alper SL, and Lencer WI (1997) The antifungal antibiotic, clotrimazole, inhibits chloride secretion by human intestinal T84 cells via blockade of distinct basolateral K+ conductances. Demonstration of efficacy in intact rabbit colon and in an in vivo mouse model of cholera. J Clin Investig 100:3111-3120

  • ↵31. 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

  • ↵32. Reich EP, Cui L, Yang L, Pugliese-Sivo C, Golovko A, Petro M, Vassileva G, Chu I, Nomeir AA, Zhang LK, et al. (2005) Blocking ion channel KCNN4 alleviates the symptoms of experimental autoimmune encephalomyelitis in mice. Eur J Immunol 35:1027-1036

  • ↵33. Mauler F, Hinz V, Horvath E, Schuhmacher J, Hofmann HA, Wirtz S, Hahn MG, and Urbahns K (2004) Selective intermediate/small-conductance calcium-activated potassium channel (KCNN4) blockers are potent and effective therapeutics in experimental brain oedema and traumatic brain injury caused by acute subdural haematoma. Eur J Neurosci 20:1761-1768

  • ↵34. Joiner WJ, Khanna R, Schlichter LC, and Kaczmarek LK (2001) Calmodulin regulates assembly and trafficking of SK4/IK1 Ca2+-activated K+ channels. J Biol Chem 276:37980-37985