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Ca2+/Calmodulin-Gated Small- and Intermediate-Conductance KCa Channels in Cardiovascular Regulation: Targets for Novel Pharmacological Treatments

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Vascular Ion Channels in Physiology and Disease

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Abstract

In vascular biology, the Ca2+/calmodulin-gated K+ channels, KCa3.1 and KCa2.3, produce membrane hyperpolarization in response to Ca2+ mobilization events and thereby initiate endothelium-derived hyperpolarization (EDH)-type of arterial dilation. The physiological relevance of this system in-vivo is evidenced by the observation that genetically encoded loss of KCa3.1 and KCa2.3 caused channel-subtype specific cardiovascular phenotypes characterized by endothelial dysfunction to receptor stimulation or mechanical stress and blood pressure alterations. From the translational perspective, KCa3.1 and KCa2.3 dysfunctions are a feature of idiopathic cardiovascular disease, chronic inflammation, atherosclerosis and organ fibrosis and KCa2.3 has been implicated in atrial fibrillation. Accordingly, KCa3.1 and KCa2.3 emerge as possible drug targets. In this chapter, we would like to highlight our recent advances in KCa3.1 and KCa2 biology, pharmacology, as well as consequences of pharmacological manipulating KCa3.1 and KCa2.3 for systemic cardiovascular regulation and cardiovascular health. Moreover, we explore impacts of innovative channel modulators on cardiac function, physical activity and behavior in keeping with the expression of KCa2-subtypes in the heart and neurons.

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Notes

  1. 1.

    Values for endothelial resting potentials vary considerably (from 0 to −89 mV), which very much depends on the preparation (intact vessel vs. cultured cells; observation by the authors’ group). In current-clamp experiments on morphologically intact endothelium of murine and human arteries we found values ranging from −25 to −45 mV that mirror the potential in smooth muscle of the same preparation (measured by sharp electrode techniques).

  2. 2.

    So far, there is no evidence that K Ca 3.1 is expressed in cardiomyocytes. In contrast, K Ca 2 channels are expressed cardiomyocytes. Moreover, K Ca 3.1 has been considered a non-neuronal channel as concluded form the absence of K Ca 3.1-mRNA in central neurons [<CitationRef CitationID="CR9" >9</Citation Ref>, <CitationRef CitationID="CR29" >29</Citation Ref>]. Interestingly, K Ca 3.1 protein has recently been documented in rat brain by immunohistochemical approaches [<CitationRef CitationID="CR122" >122</Citation Ref>]. However, we could not clearly detect K Ca 3.1 in neuronal structures (but in the blood brain barrier) in murine brain and in human post mortem material using the current IHC approaches [<CitationRef CitationID="CR70" >70</Citation Ref>]. Thus, there are apparently species differences and it remains still possible that K Ca 3.1 in neurons add to cardiovascular effects and sedation described here.

References

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

    CAS  PubMed  Google Scholar 

  2. Grgic I, Kaistha BP, Hoyer J, Kohler R. Endothelial Ca+-activated K+ channels in normal and impaired EDHF-dilator responses—relevance to cardiovascular pathologies and drug discovery. Br J Pharmacol. 2009;157:509–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Feletou M. Calcium-activated potassium channels and endothelial dysfunction: therapeutic options? Br J Pharmacol. 2009;156:545–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Feletou M, Kohler R, Vanhoutte PM. Endothelium-derived vasoactive factors and hypertension: possible roles in pathogenesis and as treatment targets. Curr Hypertens Rep. 2010;12:267–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Edwards G, Feletou M, Weston AH. Endothelium-derived hyperpolarising factors and associated pathways: a synopsis. Pflugers Arch. 2010;459:863–79.

    CAS  PubMed  Google Scholar 

  6. Feletou M, Kohler R, Vanhoutte PM. Nitric oxide: orchestrator of endothelium-dependent responses. Ann Med. 2012;44(7):694–716.

    CAS  PubMed  Google Scholar 

  7. Köhler R, Ruth P. Endothelial dysfunction and blood pressure alterations in K+-channel transgenic mice. Pflugers Arch. 2010;459:969–76.

    PubMed  Google Scholar 

  8. Wulff H, Köhler 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S, et al. International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels. Pharmacol Rev. 2005;57:463–72.

    CAS  PubMed  Google Scholar 

  10. Schmitt N, Grunnet M, Olesen SP. Cardiac potassium channel subtypes: new roles in repolarization and arrhythmia. Physiol Rev. 2014;94:609–53.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Grunnet M, Bentzen BH, Sorensen US, Diness JG. Cardiac ion channels and mechanisms for protection against atrial fibrillation. Rev Physiol Biochem Pharmacol. 2012;162:1–58.

    CAS  PubMed  Google Scholar 

  13. Yamaguchi M, Nakayama T, Fu Z, Naganuma T, Sato N, et al. Relationship between haplotypes of KCNN4 gene and susceptibility to human vascular diseases in Japanese. Med Sci Monit. 2009;15:CR389–97.

    CAS  PubMed  Google Scholar 

  14. Köhler R. Single-nucleotide polymorphisms in vascular Ca2+-activated K+-channel genes and cardiovascular disease. Pflugers Arch. 2010;460:343–51.

    PubMed  Google Scholar 

  15. Simms LA, Doecke JD, Roberts RL, Fowler EV, Zhao ZZ, et al. KCNN4 gene variant is associated with ileal Crohn’s Disease in the Australian and New Zealand population. Am J Gastroenterol. 2010;105:2209–17.

    CAS  PubMed  Google Scholar 

  16. Waeckel L, Bertin F, Clavreul N, Damery T, Kohler R, et al. Preserved regulation of renal perfusion pressure by small and intermediate conductance K channels in hypertensive mice with or without renal failure. Pflugers Arch. 2014;467:817–31.

    PubMed  Google Scholar 

  17. Haddock RE, Grayson TH, Morris MJ, Howitt L, Chadha PS, et al. Diet-induced obesity impairs endothelium-derived hyperpolarization via altered potassium channel signaling mechanisms. PLoS One. 2011;6:e16423.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wulff H, Castle NA. Therapeutic potential of KCa3.1 blockers: recent advances and promising trends. Expert Rev Clin Pharmacol. 2010;3:385–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kaczorowski GJ, Knaus HG, Leonard RJ, McManus OB, Garcia ML. High-conductance calcium-activated potassium channels; structure, pharmacology, and function. J Bioenerg Biomembr. 1996;28:255–67.

    CAS  PubMed  Google Scholar 

  20. Kaczmarek LK. Slack, slick and sodium-activated potassium channels. ISRN Neurosci. 2013;2013:354262.

    PubMed  PubMed Central  Google Scholar 

  21. Plüger S, Faulhaber J, Furstenau M, Lohn M, Waldschutz R, et al. Mice with disrupted BK channel beta1 subunit gene feature abnormal Ca(2+) spark/STOC coupling and elevated blood pressure. Circ Res. 2000;87:E53–60.

    PubMed  Google Scholar 

  22. Gollasch M, Ried C, Bychkov R, Luft FC, Haller H. K+ currents in human coronary artery vascular smooth muscle cells. Circ Res. 1996;78:676–88.

    CAS  PubMed  Google Scholar 

  23. Hill-Eubanks DC, Werner ME, Heppner TJ, Nelson MT. Calcium signaling in smooth muscle. Cold Spring Harb Perspect Biol. 2011;3:a004549.

    PubMed  PubMed Central  Google Scholar 

  24. Brenner R, Perez GJ, Bonev AD, Eckman DM, Kosek JC, et al. Vasoregulation by the beta1 subunit of the calcium-activated potassium channel. Nature. 2000;407:870–6.

    CAS  PubMed  Google Scholar 

  25. Brakemeier S, Eichler I, Knorr A, Fassheber T, Kohler R, et al. Modulation of Ca2+-activated K+ channel in renal artery endothelium in situ by nitric oxide and reactive oxygen species. Kidney Int. 2003;64:199–207.

    CAS  PubMed  Google Scholar 

  26. Bychkov R, Burnham MP, Richards GR, Edwards G, Weston AH, et al. Characterization of a charybdotoxin-sensitive intermediate conductance Ca2+-activated K+ channel in porcine coronary endothelium: relevance to EDHF. Br J Pharmacol. 2002;137:1346–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Fernandez-Fernandez JM, Tomas M, Vazquez E, Orio P, Latorre R, et al. Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension. J Clin Invest. 2004;113:1032–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Tomas M, Vazquez E, Fernandez-Fernandez JM, Subirana I, Plata C, et al. Genetic variation in the KCNMA1 potassium channel alpha subunit as risk factor for severe essential hypertension and myocardial infarction. J Hypertens. 2008;26:2147–53.

    CAS  PubMed  Google Scholar 

  29. Ishii TM, Silvia C, Hirschberg B, Bond CT, Adelman JP, et al. A human intermediate conductance calcium-activated potassium channel. Proc Natl Acad Sci U S A. 1997;94:11651–6.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  31. Alvarez J, Montero M, Garcia-Sancho J. High affinity inhibition of Ca(2+)-dependent K+ channels by cytochrome P-450 inhibitors. J Biol Chem. 1992;267:11789–93.

    CAS  PubMed  Google Scholar 

  32. Knaus HG, McManus OB, Lee SH, Schmalhofer WA, Garcia-Calvo M, et al. Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels. Biochemistry. 1994;33:5819–28.

    CAS  PubMed  Google Scholar 

  33. Rosa JC, Galanakis D, Ganellin CR, Dunn PM, Jenkinson DH. Bis-quinolinium cyclophanes: 6,10-diaza-3(1,3),8(1,4)-dibenzena-1,5(1,4)-diquinolinacyclodecaphane (UCL 1684), the first nanomolar, non-peptidic blocker of the apamin-sensitive Ca2+-activated K+ channel. J Med Chem. 1998;41:2–5.

    CAS  PubMed  Google Scholar 

  34. Marchenko SM, Sage SO. Calcium-activated potassium channels in the endothelium of intact rat aorta. J Physiol. 1996;492(Pt 1):53–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Van Renterghem C, Vigne P, Frelin C. A charybdotoxin-sensitive, Ca(2+)-activated K+ channel with inward rectifying properties in brain microvascular endothelial cells: properties and activation by endothelins. J Neurochem. 1995;65:1274–81.

    PubMed  Google Scholar 

  36. Cai S, Garneau L, Sauve R. Single-channel characterization of the pharmacological properties of the K(Ca2+) channel of intermediate conductance in bovine aortic endothelial cells. J Membr Biol. 1998;163:147–58.

    CAS  PubMed  Google Scholar 

  37. Köhler R, Distler A, Hoyer J. Increased mechanosensitive currents in aortic endothelial cells from genetically hypertensive rats. J Hypertens. 1999;17:365–71.

    PubMed  Google Scholar 

  38. Burnham MP, Bychkov R, Feletou M, Richards GR, Vanhoutte PM, et al. Characterization of an apamin-sensitive small-conductance Ca(2+)-activated K(+) channel in porcine coronary artery endothelium: relevance to EDHF. Br J Pharmacol. 2002;135:1133–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Eichler I, Wibawa J, Grgic I, Knorr A, Brakemeier S, et al. Selective blockade of endothelial Ca2+-activated small- and intermediate-conductance K+-channels suppresses EDHF-mediated vasodilation. Br J Pharmacol. 2003;138:594–601.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Köhler R, Degenhardt C, Kuhn M, Runkel N, Paul M, et al. Expression and function of endothelial Ca2+-activated K+ channels in human mesenteric artery: a single-cell reverse transcriptase-polymerase chain reaction and electrophysiological study in situ. Circ Res. 2000;87:496–503.

    PubMed  Google Scholar 

  41. Chadha PS, Liu L, Rikard-Bell M, Senadheera S, Howitt L, et al. Endothelium-dependent vasodilation in human mesenteric artery is primarily mediated by myoendothelial gap junctions intermediate conductance calcium-activated K+ channel and nitric oxide. J Pharmacol Exp Ther. 2011;336:701–8.

    CAS  PubMed  Google Scholar 

  42. Fisslthaler B, Popp R, Kiss L, Potente M, Harder DR, et al. Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature. 1999;401:493–7.

    CAS  PubMed  Google Scholar 

  43. Ng KF, Leung SW, Man RY, Vanhoutte PM. Endothelium-derived hyperpolarizing factor mediated relaxations in pig coronary arteries do not involve Gi/o proteins. Acta Pharmacol Sin. 2008;29:1419–24.

    CAS  PubMed  Google Scholar 

  44. Olivan-Viguera A, Valero MS, Murillo MD, Wulff H, Garcia-Otin AL, et al. Novel phenolic inhibitors of small/intermediate-conductance Ca(2)(+)-activated K(+) channels, KCa3.1 and KCa2.3. PLoS One. 2013;8:e58614.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Randriamboavonjy V, Kiss L, Falck JR, Busse R, Fleming I. The synthesis of 20-HETE in small porcine coronary arteries antagonizes EDHF-mediated relaxation. Cardiovasc Res. 2005;65:487–94.

    CAS  PubMed  Google Scholar 

  46. Kacik M, Olivan-Viguera A, Kohler R. Modulation of KCa3.1 channels by eicosanoids, omega-3 fatty acids, and molecular determinants. PLoS One. 2014;9:e112081.

    PubMed  PubMed Central  Google Scholar 

  47. Si H, Heyken WT, Wölfle SE, Tysiac M, Schubert R, et al. Impaired endothelium-derived hyperpolarizing factor-mediated dilations and increased blood pressure in mice deficient of the intermediate-conductance Ca2+-activated K+ channel. Circ Res. 2006;99:537–44.

    CAS  PubMed  Google Scholar 

  48. Bond CT, Sprengel R, Bissonnette JM, Kaufmann WA, Pribnow D, et al. Respiration and parturition affected by conditional overexpression of the Ca2+-activated K+ channel subunit, SK3. Science. 2000;289:1942–6.

    CAS  PubMed  Google Scholar 

  49. Taylor MS, Bonev AD, Gross TP, Eckman DM, Brayden JE, et al. Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure. Circ Res. 2003;93:124–31.

    CAS  PubMed  Google Scholar 

  50. Brähler S, Kaistha A, Schmidt VJ, Wolfle SE, Busch C, 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.

    PubMed  Google Scholar 

  51. Wolfle SE, Schmidt VJ, Hoyer J, Kohler R, de Wit C. Prominent role of KCa3.1 in endothelium-derived hyperpolarizing factor-type dilations and conducted responses in the microcirculation in vivo. Cardiovasc Res. 2009;82:476–83.

    PubMed  Google Scholar 

  52. Milkau M, Kohler R, de Wit C. Crucial importance of the endothelial K+ channel SK3 and connexin40 in arteriolar dilations during skeletal muscle contraction. FASEB J. 2010;24:3572–9.

    CAS  PubMed  Google Scholar 

  53. Hasenau AL, Nielsen G, Morisseau C, Hammock BD, Wulff H, et al. Improvement of endothelium-dependent vasodilations by SKA-31 and SKA-20, activators of small- and intermediate-conductance Ca2+-activated K+-channels. Acta Physiol (Oxf). 2011;203:117–26.

    CAS  Google Scholar 

  54. Köhler R, Heyken WT, Heinau P, Schubert R, Si H, et al. Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation. Arterioscler Thromb Vasc Biol. 2006;26:1495–502.

    PubMed  Google Scholar 

  55. Qian X, Francis M, Kohler R, Solodushko V, Lin M, et al. Positive feedback regulation of agonist-stimulated endothelial Ca2+ dynamics by KCa3.1 channels in mouse mesenteric arteries. Arterioscler Thromb Vasc Biol. 2014;34:127–35.

    CAS  PubMed  Google Scholar 

  56. Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, et al. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature. 2003;424:434–8.

    CAS  PubMed  Google Scholar 

  57. Ledoux J, Taylor MS, Bonev AD, Hannah RM, Solodushko V, et al. Functional architecture of inositol 1,4,5-trisphosphate signaling in restricted spaces of myoendothelial projections. Proc Natl Acad Sci U S A. 2008;105:9627–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Hill CE. Tudor Griffith, gap junctions and conducted vasodilatation: electromechanical coupling back in the limelight. J Cardiovasc Pharmacol. 2013;61:93–101.

    CAS  PubMed  Google Scholar 

  59. de Wit C, Griffith TM. Connexins and gap junctions in the EDHF phenomenon and conducted vasomotor responses. Pflugers Arch. 2010;459:897–914.

    PubMed  Google Scholar 

  60. Billaud M, Lohman AW, Johnstone SR, Biwer LA, Mutchler S, et al. Regulation of cellular communication by signaling microdomains in the blood vessel wall. Pharmacol Rev. 2014;66:513–69.

    PubMed  PubMed Central  Google Scholar 

  61. Sandow SL, Neylon CB, Chen MX, Garland CJ. Spatial separation of endothelial small- and intermediate-conductance calcium-activated potassium channels (KCa) and connexins: possible relationship to vasodilator function? J Anat. 2006;209:689–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Ma X, Du J, Zhang P, Deng J, Liu J, et al. Functional role of TRPV4-KCa2.3 signaling in vascular endothelial cells in normal and streptozotocin-induced diabetic rats. Hypertension. 2013;62:134–9.

    PubMed  Google Scholar 

  63. Berrout J, Mamenko M, Zaika OL, Chen L, Zang W, et al. Emerging role of the calcium-activated, small conductance, SK3 K+ channel in distal tubule function: regulation by TRPV4. PLoS One. 2014;9:e95149.

    PubMed  PubMed Central  Google Scholar 

  64. Sukumaran SV, Singh TU, Parida S, Narasimha Reddy CE, Thangamalai R, et al. TRPV4 channel activation leads to endothelium-dependent relaxation mediated by nitric oxide and endothelium-derived hyperpolarizing factor in rat pulmonary artery. Pharmacol Res. 2013;78:18–27.

    CAS  PubMed  Google Scholar 

  65. Hoyer J, Kohler R, Distler A. Mechanosensitive Ca2+ oscillations and STOC activation in endothelial cells. FASEB J. 1998;12:359–66.

    CAS  PubMed  Google Scholar 

  66. Sonkusare SK, Bonev AD, Ledoux J, Liedtke W, Kotlikoff MI, et al. Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. Science. 2012;336:597–601.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Hartmannsgruber V, Heyken WT, Kacik M, Kaistha A, Grgic I, et al. Arterial response to shear stress critically depends on endothelial TRPV4 expression. PLoS One. 2007;2:e827.

    PubMed  PubMed Central  Google Scholar 

  68. Saliez J, Bouzin C, Rath G, Ghisdal P, Desjardins F, et al. Role of caveolar compartmentation in endothelium-derived hyperpolarizing factor-mediated relaxation: Ca2+ signals and gap junction function are regulated by caveolin in endothelial cells. Circulation. 2008;117:1065–74.

    CAS  PubMed  Google Scholar 

  69. Dominguez Rieg JA, Burt JM, Ruth P, Rieg T. P2Y receptor activation decreases blood pressure via intermediate conductance potassium channels and connexin 37. Acta Physiol (Oxf). 2014;213:628–41.

    Google Scholar 

  70. Lambertsen KL, Gramsbergen JB, Sivasaravanaparan M, Ditzel N, Sevelsted-Moller LM, et al. Genetic KCa3.1-deficiency produces locomotor hyperactivity and alterations in cerebral monoamine levels. PLoS One. 2012;7:e47744.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Liang Z, Chen L, McClafferty H, Lukowski R, Macgregor D, et al. Control of HPA stress axis activity by the intermediate conductance calcium-activated potassium channel, SK4. J Physiol. 2011;589:5965–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Grgic I, Kaistha BP, Paschen S, Kaistha A, Busch C, et al. Disruption of the Gardos channel (KCa3.1) in mice causes subtle erythrocyte macrocytosis and progressive splenomegaly. Pflugers Arch. 2009;458:291–302.

    CAS  PubMed  Google Scholar 

  73. Rada CC, Pierce SL, Nuno DW, Zimmerman K, Lamping KG, et al. Overexpression of the SK3 channel alters vascular remodeling during pregnancy, leading to fetal demise. Am J Physiol Endocrinol Metab. 2012;303:E825–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Wandall-Frostholm C, Skaarup LM, Sadda V, Nielsen G, Hedegaard ER, et al. Pulmonary hypertension in wild type mice and animals with genetic deficit in KCa2.3 and KCa3.1 channels. PLoS One. 2014;9:e97687.

    PubMed  PubMed Central  Google Scholar 

  75. Mahida S, Mills RW, Tucker NR, Simonson B, Macri V, et al. Overexpression of KCNN3 results in sudden cardiac death. Cardiovasc Res. 2014;101:326–34.

    CAS  PubMed  Google Scholar 

  76. Köhler R, Wulff H, Eichler I, Kneifel M, Neumann D, et al. Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis. Circulation. 2003;108:1119–25.

    PubMed  Google Scholar 

  77. Tharp DL, Wamhoff BR, Wulff H, Raman G, Cheong A, et al. Local delivery of the KCa3.1 blocker, TRAM-34, prevents acute angioplasty-induced coronary smooth muscle phenotypic modulation and limits stenosis. Arterioscler Thromb Vasc Biol. 2008;28:1084–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Toyama K, Wulff H, Chandy KG, Azam P, Raman G, et al. The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans. J Clin Invest. 2008;118:3025–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Roach KM, Wulff H, Feghali-Bostwick C, Amrani Y, Bradding P. Increased constitutive inverted question markSMA and Smad2/3 expression in idiopathic pulmonary fibrosis myofibroblasts is K Ca 31-dependent. Respir Res. 2014;15:155.

    PubMed  PubMed Central  Google Scholar 

  80. Grgic I, Kiss E, Kaistha BP, Busch C, Kloss M, et al. Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels. Proc Natl Acad Sci U S A. 2009;106:14518–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Huang C, Shen S, Ma Q, Gill A, Pollock CA, et al. KCa3.1 mediates activation of fibroblasts in diabetic renal interstitial fibrosis. Nephrol Dial Transplant. 2014;29:313–24.

    CAS  PubMed  Google Scholar 

  82. Freise C, Heldwein S, Erben U, Hoyer J, Kohler R, et al. K-channel inhibition reduces portal perfusion pressure in fibrotic rats and fibrosis associated characteristics of hepatic stellate cells. Liver Int. 2014;35:1244–52.

    PubMed  Google Scholar 

  83. Chen YJ, Lam J, Gregory CR, Schrepfer S, Wulff H. The Ca(2)(+)-activated K(+) channel KCa3.1 as a potential new target for the prevention of allograft vasculopathy. PLoS One. 2013;8:e81006.

    PubMed  PubMed Central  Google Scholar 

  84. Grgic I, Wulff H, Eichler I, Flothmann C, Kohler R, et al. Blockade of T-lymphocyte KCa3.1 and Kv1.3 channels as novel immunosuppression strategy to prevent kidney allograft rejection. Transplant Proc. 2009;41:2601–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Hua X, Deuse T, Chen YJ, Wulff H, Stubbendorff M, et al. The potassium channel KCa3.1 as new therapeutic target for the prevention of obliterative airway disease. Transplantation. 2013;95:285–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Si H, Grgic I, Heyken WT, Maier T, Hoyer J, et al. Mitogenic modulation of Ca2+-activated K+ channels in proliferating A7r5 vascular smooth muscle cells. Br J Pharmacol. 2006;148:909–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Cheong A, Bingham AJ, Li J, Kumar B, Sukumar P, et al. Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation. Mol Cell. 2005;20:45–52.

    CAS  PubMed  Google Scholar 

  88. Brakemeier S, Kersten A, Eichler I, Grgic I, Zakrzewicz A, et al. Shear stress-induced up-regulation of the intermediate-conductance Ca(2+)-activated K(+) channel in human endothelium. Cardiovasc Res. 2003;60:488–96.

    CAS  PubMed  Google Scholar 

  89. Takai J, Santu A, Zheng H, Koh SD, Ohta M, et al. Laminar shear stress upregulates endothelial Ca(2)(+)-activated K(+) channels KCa2.3 and KCa3.1 via a Ca(2)(+)/calmodulin-dependent protein kinase kinase/Akt/p300 cascade. Am J Physiol Heart Circ Physiol. 2013;305:H484–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Köhler R, Brakemeier S, Kuhn M, Behrens C, Real R, et al. Impaired hyperpolarization in regenerated endothelium after balloon catheter injury. Circ Res. 2001;89:174–9.

    PubMed  Google Scholar 

  91. Köhler R, Eichler I, Schonfelder H, Grgic I, Heinau P, et al. Impaired EDHF-mediated vasodilation and function of endothelial Ca-activated K channels in uremic rats. Kidney Int. 2005;67:2280–7.

    PubMed  Google Scholar 

  92. Chennupati R, Lamers WH, Koehler SE, De Mey JG. Endothelium-dependent hyperpolarization-related relaxations diminish with age in murine saphenous arteries of both sexes. Br J Pharmacol. 2013;169:1486–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Yap FC, Taylor MS, Lin MT. Ovariectomy-induced reductions in endothelial SK3 channel activity and endothelium-dependent vasorelaxation in murine mesenteric arteries. PLoS One. 2014;9:e104686.

    PubMed  PubMed Central  Google Scholar 

  94. Climent B, Moreno L, Martinez P, Contreras C, Sanchez A, et al. Upregulation of SK3 and IK1 channels contributes to the enhanced endothelial calcium signaling and the preserved coronary relaxation in obese Zucker rats. PLoS One. 2014;9:e109432.

    PubMed  PubMed Central  Google Scholar 

  95. Chadha PS, Haddock RE, Howitt L, Morris MJ, Murphy TV, et al. Obesity up-regulates intermediate conductance calcium-activated potassium channels and myoendothelial gap junctions to maintain endothelial vasodilator function. J Pharmacol Exp Ther. 2010;335:284–93.

    CAS  PubMed  Google Scholar 

  96. Chantome A, Potier-Cartereau M, Clarysse L, Fromont G, Marionneau-Lambot S, et al. Pivotal role of the lipid Raft SK3-Orai1 complex in human cancer cell migration and bone metastases. Cancer Res. 2013;73:4852–61.

    CAS  PubMed  Google Scholar 

  97. Turner KL, Honasoge A, Robert SM, McFerrin MM, Sontheimer H. A proinvasive role for the Ca(2+)-activated K(+) channel KCa3.1 in malignant glioma. Glia. 2014;62:971–81.

    PubMed  PubMed Central  Google Scholar 

  98. Grossinger EM, Weiss L, Zierler S, Rebhandl S, Krenn PW, et al. Targeting proliferation of chronic lymphocytic leukemia (CLL) cells through KCa3.1 blockade. Leukemia. 2014;28:954–8.

    CAS  PubMed  Google Scholar 

  99. D’Alessandro G, Catalano M, Sciaccaluga M, Chece G, Cipriani R, et al. KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo. Cell Death Dis. 2013;4:e773.

    PubMed  PubMed Central  Google Scholar 

  100. Ouadid-Ahidouch H, Ahidouch A. K(+) channels and cell cycle progression in tumor cells. Front Physiol. 2013;4:220.

    PubMed  PubMed Central  Google Scholar 

  101. Huang X, Jan LY. Targeting potassium channels in cancer. J Cell Biol. 2014;206:151–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Koch Hansen L, Sevelsted-Moller L, Rabjerg M, Larsen D, Hansen TP, et al. Expression of T-cell KV1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis. J Crohns Colitis. 2014;8:1378–91.

    PubMed  Google Scholar 

  103. Chen YJ, Raman G, Bodendiek S, O’Donnell ME, Wulff H. The KCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a rat model of ischemia/reperfusion stroke. J Cereb Blood Flow Metab. 2011;31:2363–74.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Chen YJ, Wallace BK, Yuen N, Jenkins DP, Wulff H, et al. Blood-brain barrier KCa3.1 channels: evidence for a role in brain na uptake and edema in ischemic stroke. Stroke. 2015;46(1):237–44.

    CAS  PubMed  Google Scholar 

  106. Mauler F, Hinz V, Horvath E, Schuhmacher J, Hofmann HA, et al. 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. 2004;20:1761–8.

    PubMed  Google Scholar 

  107. Ataga KI, Reid M, Ballas SK, Yasin Z, Bigelow C, et al. Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043). Br J Haematol. 2011;153:92–104.

    CAS  PubMed  Google Scholar 

  108. Bouhy D, Ghasemlou N, Lively S, Redensek A, Rathore KI, et al. Inhibition of the Ca2+-dependent K+ channel, KCNN4/KCa3.1, improves tissue protection and locomotor recovery after spinal cord injury. J Neurosci. 2011;31:16298–308.

    CAS  PubMed  Google Scholar 

  109. Schlichter LC, Kaushal V, Moxon-Emre I, Sivagnanam V, Vincent C. The Ca2+ activated SK3 channel is expressed in microglia in the rat striatum and contributes to microglia-mediated neurotoxicity in vitro. J Neuroinflammation. 2010;7:4.

    PubMed  PubMed Central  Google Scholar 

  110. Maezawa I, Zimin PI, Wulff H, Jin LW. Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity. J Biol Chem. 2011;286:3693–706.

    CAS  PubMed  Google Scholar 

  111. Sankaranarayanan A, Raman G, Busch C, Schultz T, Zimin PI, 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.

    CAS  PubMed  Google Scholar 

  112. Mishra RC, Belke D, Wulff H, Braun AP. SKA-31, a novel activator of SK(Ca) and IK(Ca) channels, increases coronary flow in male and female rat hearts. Cardiovasc Res. 2013;97:339–48.

    CAS  PubMed  Google Scholar 

  113. Damkjaer M, Nielsen G, Bodendiek S, Staehr M, Gramsbergen JB, et al. Pharmacological activation of KCa3.1/KCa2.3 channels produces endothelial hyperpolarization and lowers blood pressure in conscious dogs. Br J Pharmacol. 2012;165:223–34.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  115. Radtke J, Schmidt K, Wulff H, Kohler R, de Wit C. Activation of KCa3.1 by SKA-31 induces arteriolar dilatation and lowers blood pressure in normo- and hypertensive connexin40-deficient mice. Br J Pharmacol. 2013;170:293–303.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Waeckel L, Badier-Commander C, Damery T, Kohler R, Sansilvestri-Morel P, et al. Vascular dysfunctions in the isolated aorta of double-transgenic hypertensive mice developing aortic aneurysm. Pflugers Arch. 2014;467:1945–63.

    PubMed  Google Scholar 

  117. Soder RP, Parajuli SP, Hristov KL, Rovner ES, Petkov GV. SK channel-selective opening by SKA-31 induces hyperpolarization and decreases contractility in human urinary bladder smooth muscle. Am J Physiol Regul Integr Comp Physiol. 2013;304:R155–63.

    CAS  PubMed  Google Scholar 

  118. Zhang M, Pascal JM, Schumann M, Armen RS, Zhang JF. Identification of the functional binding pocket for compounds targeting small-conductance Ca(2)(+)-activated potassium channels. Nat Commun. 2012;3:1021.

    PubMed  PubMed Central  Google Scholar 

  119. Zhang M, Pascal JM, Zhang JF. Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca(2)(+)-sensing and SK channel activation. Proc Natl Acad Sci U S A. 2013;110:4828–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Cui M, Qin G, Yu K, Bowers MS, Zhang M. Targeting the small- and intermediate-conductance Ca-activated potassium channels: the drug-binding pocket at the channel/calmodulin interface. Neurosignals. 2014;22:65–78.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  122. Engbers JD, Anderson D, Asmara H, Rehak R, Mehaffey WH, et al. Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells. Proc Natl Acad Sci U S A. 2012;109:2601–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Coleman N, Nguyen HM, Cao Z, Brown BM, Jenkins DP, et al. The riluzole derivative 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a mixed K2 activator and Na blocker, is a potent novel anticonvulsant. Neurotherapeutics. 2014;12:234–49.

    PubMed Central  Google Scholar 

  124. Grgic I, Eichler I, Heinau P, Si H, Brakemeier S, et al. 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. 2005;25:704–9.

    CAS  PubMed  Google Scholar 

  125. Van Der Velden J, Sum G, Barker D, Koumoundouros E, Barcham G, et al. K(Ca)3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma. PLoS One. 2013;8:e66886.

    Google Scholar 

  126. Köhler R, Kaistha BP, Wulff H. Vascular KCa-channels as therapeutic targets in hypertension and restenosis disease. Expert Opin Ther Targets. 2010;14:143–55.

    PubMed  PubMed Central  Google Scholar 

  127. Lamoral-Theys D, Pottier L, Kerff F, Dufrasne F, Proutiere F, et al. Simple di- and trivanillates exhibit cytostatic properties toward cancer cells resistant to pro-apoptotic stimuli. Bioorg Med Chem. 2010;18:3823–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Olivan-Viguera A, Valero MS, Coleman N, Brown BM, Laria C, et al. A novel pan-negative-gating modulator of KCa2/3 channels, the fluoro-di-benzoate, RA-2, inhibits EDH-type relaxation in coronary artery and produces bradycardia in vivo. Mol Pharmacol. 2015;87:1–12.

    Google Scholar 

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Acknowledgements

The authors are supported by the Deutsche Forschungsgemeinschaft (KO1899/11-1), the Danish Heart Foundation, European Community (FP7-PEOPLE Project 321721), Department of Industry & Innovation, Government of Aragon (GIPASC-B105), and the Fondo de Investigación Sanitaria (Red HERACLES RD12/0042/0014).

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Authors and Affiliations

  1. Fundación Agencia Aragonesa para la Investigación y Desarrollo (ARAID), Zaragoza, Spain

    Ralf Köhler

  2. Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Paseo Isabel la Católica, 1-3, 50009, Zaragoza, Spain

    Ralf Köhler

  3. Aragon Institute of Health Sciences & IIS Aragon, 50009, Zaragoza, Spain

    Ralf Köhler & Aida Olivan-Viguera

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  1. Ralf Köhler
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  2. Aida Olivan-Viguera
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Correspondence to Ralf Köhler .

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Editors and Affiliations

  1. University of Illinois at Chicago, Chicago, Illinois, USA

    Irena Levitan, PhD

  2. The University of Tennessee, Memphis, Tennessee, USA

    Alex M. Dopico, MD, PhD

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Köhler, R., Olivan-Viguera, A. (2016). Ca2+/Calmodulin-Gated Small- and Intermediate-Conductance KCa Channels in Cardiovascular Regulation: Targets for Novel Pharmacological Treatments. In: Levitan, PhD, I., Dopico, MD, PhD, A. (eds) Vascular Ion Channels in Physiology and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-29635-7_5

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