Abstract
In the cardiovascular system, Ca2+-activated K+-channels (KCa) are considered crucial mediators in the control of vascular tone and blood pressure by modulating the membrane potential and shaping Ca2+-dependent contraction. Vascular smooth muscle cells express the BKCa channel which fine-tunes contractility by providing a negative feedback on Ca2+-elevations. BKCa channel's ion-conducting α-subunit is encoded by the KCa1.1 gene, and the accessory and Ca2+-sensitivity modulating β1-subunit is encoded by the KCNMB1 gene. Vascular endothelial cells express the calmodulin-gated KCa channels IKCa (encoded by the KCa3.1 gene) and SKCa (encoded by the KCa2.3 gene). These two channels mediate endothelial hyperpolarization and initiate the endothelium-derived hyperpolarizing factor-dilator response. Considering these essential roles of KCa in arterial function, mutations in KCa genes have been suspected to contribute to cardiovascular disease in humans. So far, DNA sequence analysis in the population and patient cohorts has identified single-nucleotide polymorphisms (SNPs) in the BKCa β1-subunit gene as well as in the α-subunit gene (KCa1.1). Some of these SNPs produce amino acid exchanges and evoke alterations of channel functions (“gain-of-function” as well as “loss-of-function”). Moreover, the epidemiological studies showed that the presence of the E65K polymorphism in, e.g., BKCa β1-subunit gene (producing a “gain-of-function”) lowers the prevalence for severe hypertension and myocardial infarction. Other SNPs in the BKCa α-subunit gene and also in the KCa3.1 gene expressed in the endothelium have been suggested to increase the risk of cardiovascular disease. These findings from sequence analysis of human KCa genes, and epidemiological studies thus provide evidence that genetic variations and mutations in KCa channel genes contribute to human cardiovascular disease.
Similar content being viewed by others
References
Bolotina VM, Najibi S, Palacino JJ, Pagano PJ, Cohen RA (1994) Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 368:850–853
Bond CT, Sprengel R, Bissonnette JM, Kaufmann WA, Pribnow D, Neelands T, Storck T, Baetscher M, Jerecic J, Maylie J, Knaus HG, Seeburg PH, Adelman JP (2000) Respiration and parturition affected by conditional overexpression of the Ca2+-activated K+ channel subunit, SK3. Science 289:1942–1946
Brahler S, Kaistha A, Schmidt VJ, Wolfle SE, Busch C, Kaistha BP, Kacik M, Hasenau AL, Grgic I, Si H, Bond CT, Adelman JP, Wulff H, de Wit C, Hoyer J, Kohler R (2009) Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension. Circulation 119:2323–2332
Brayden JE, Quayle JM, Standen NB, Nelson MT (1991) Role of potassium channels in the vascular response to endogenous and pharmacological vasodilators. Blood Vessels 28:147–153
Brenner R, Perez GJ, Bonev AD, Eckman DM, Kosek JC, Wiler SW, Patterson AJ, Nelson MT, Aldrich RW (2000) Vasoregulation by the beta1 subunit of the calcium-activated potassium channel. Nature 407:870–876
Burnham MP, Bychkov R, Feletou M, Richards GR, Vanhoutte PM, Weston AH, Edwards G (2002) Characterization of an apamin-sensitive small-conductance Ca(2+)-activated K(+) channel in porcine coronary artery endothelium: relevance to EDHF. Br J Pharmacol 135:1133–1143
Busse R, Edwards G, Feletou M, Fleming I, Vanhoutte PM, Weston AH (2002) EDHF: bringing the concepts together. Trends Pharmacol Sci 23:374–380
Cai S, Garneau L, Sauve R (1998) Single-channel characterization of the pharmacological properties of the K(Ca2+) channel of intermediate conductance in bovine aortic endothelial cells. J Membr Biol 163:147–158
Cheong A, Bingham AJ, Li J, Kumar B, Sukumar P, Munsch C, Buckley NJ, Neylon CB, Porter KE, Beech DJ, Wood IC (2005) Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation. Mol Cell 20:45–52
Coleman HA, Tare M, Parkington HC (2004) Endothelial potassium channels, endothelium-dependent hyperpolarization and the regulation of vascular tone in health and disease. Clin Exp Pharmacol Physiol 31:641–649
De Mey JG, Claeys M, Vanhoutte PM (1982) Endothelium-dependent inhibitory effects of acetylcholine, adenosine triphosphate, thrombin and arachidonic acid in the canine femoral artery. J Pharmacol Exp Ther 222:166–173
Diaz L, Meera P, Amigo J, Stefani E, Alvarez O, Toro L, Latorre R (1998) Role of the S4 segment in a voltage-dependent calcium-sensitive potassium (hSlo) channel. J Biol Chem 273:32430–32436
Dimitropoulou C, White RE, Ownby DR, Catravas JD (2005) Estrogen reduces carbachol-induced constriction of asthmatic airways by stimulating large-conductance voltage and calcium-dependent potassium channels. Am J Respir Cell Mol Biol 32:239–247
Du W, Bautista JF, Yang H, Diez-Sampedro A, You SA, Wang L, Kotagal P, Luders HO, Shi J, Cui J, Richerson GB, Wang QK (2005) Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet 37:733–738
Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH (1998) K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396:269–272
Eichler I, Wibawa J, Grgic I, Knorr A, Brakemeier S, Pries AR, Hoyer J, 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
Feletou M (2009) Calcium-activated potassium channels and endothelial dysfunction: therapeutic options? Br J Pharmacol 156:545–562
Feletou M, Vanhoutte PM (1988) Endothelium-dependent hyperpolarization of canine coronary smooth muscle. Br J Pharmacol 93:515–524
Feletou M, Vanhoutte PM (2006) Endothelium-derived hyperpolarizing factor: where are we now? Arterioscler Thromb Vasc Biol 26:1215–1225
Feletou M, Vanhoutte PM (2006) Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol 291:H985–H1002
Feng J, Liu Y, Clements RT, Sodha NR, Khabbaz KR, Senthilnathan V, Nishimura KK, Alper SL, Sellke FW (2008) Calcium-activated potassium channels contribute to human coronary microvascular dysfunction after cardioplegic arrest. Circulation 118:S46–S51
Fernandez-Fernandez JM, Tomas M, Vazquez E, Orio P, Latorre R, Senti M, Marrugat J, Valverde MA (2004) Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension. J Clin Invest 113:1032–1039
Gollasch M, Lohn M, Furstenau M, Nelson MT, Luft FC, Haller H (2000) Ca2+ channels, “quantized” Ca2+ release, and differentiation of myocytes in the cardiovascular system. J Hypertens 18:989–998
Gollasch M, Lohn M, Furstenau M, Nelson MT, Luft FC, Haller H (2000) Ca2+ channels, Ca2+ sparks, and regulation of arterial smooth muscle function. Z Kardiol 89(Suppl 2):15–19
Gollasch M, Tank J, Luft FC, Jordan J, Maass P, Krasko C, Sharma AM, Busjahn A, Bahring S (2002) The BK channel beta1 subunit gene is associated with human baroreflex and blood pressure regulation. J Hypertens 20:927–933
Grgic I, Kaistha BP, Hoyer J, Kohler R (2009) Endothelial Ca(2+)-activated K(+) channels in normal and impaired EDHF-dilator responses—relevance to cardiovascular pathologies and drug discovery. Br J Pharmacol 157:509–526
Grgic I, Kaistha BP, Paschen S, Kaistha A, Busch C, Si H, Kohler K, Elsasser HP, Hoyer J, Kohler R (2009) Disruption of the Gardos channel (KCa3.1) in mice causes subtle erythrocyte macrocytosis and progressive splenomegaly. Pflugers Arch 458:291–302
Griffith TM (2004) Endothelium-dependent smooth muscle hyperpolarization: do gap junctions provide a unifying hypothesis? Br J Pharmacol 141:881–903
Grimm PR, Irsik DL, Settles DC, Holtzclaw JD, Sansom SC (2009) Hypertension of Kcnmb1-/- is linked to deficient K secretion and aldosteronism. Proc Natl Acad Sci USA 106:11800–11805
Ishii TM, Silvia C, Hirschberg B, Bond CT, Adelman JP, Maylie J (1997) A human intermediate conductance calcium-activated potassium channel. Proc Natl Acad Sci USA 94:11651–11656
Jiang Z, Wallner M, Meera P, Toro L (1999) Human and rodent MaxiK channel beta-subunit genes: cloning and characterization. Genomics 55:57–67
Joiner WJ, Wang LY, Tang MD, Kaczmarek LK (1997) hSK4, a member of a novel subfamily of calcium-activated potassium channels. Proc Natl Acad Sci USA 94:11013–11018
Kaczorowski GJ, Knaus HG, Leonard RJ, McManus OB, Garcia ML (1996) High-conductance calcium-activated potassium channels; structure, pharmacology, and function. J Bioenerg Biomembr 28:255–267
Kelley-Hedgepeth A, Peter I, Montefusco MC, Levy D, Benjamin EJ, Vasan RS, Mendelsohn ME, Housman D, Huggins GS, Mitchell GF (2009) The KCNMB1 E65K variant is associated with reduced central pulse pressure in the community-based Framingham Offspring Cohort. J Hypertens 27:55–60
Kelley-Hedgepeth A, Peter I, Kip K, Montefusco M, Kogan S, Cox D, Ordovas J, Levy D, Reis S, Mendelsohn M, Housman D, Huggins G (2008) The protective effect of KCNMB1 E65K against hypertension is restricted to blood pressure treatment with beta-blockade. J Hum Hypertens 22:512–515
Kokubo Y, Iwai N, Tago N, Inamoto N, Okayama A, Yamawaki H, Naraba H, Tomoike H (2005) Association analysis between hypertension and CYBA, CLCNKB, and KCNMB1 functional polymorphisms in the Japanese population—the Suita Study. Circ J 69:138–142
Kundu P, Alioua A, Stefani E, Toro L (2007) Regulation of mouse Slo gene expression: multiple promoters, transcription start sites, and genomic action of estrogen. J Biol Chem 282:27478–27492
Köhler M, Hirschberg B, Bond CT, Kinzie JM, Marrion NV, Maylie J, Adelman JP (1996) Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273:1709–1714
Köhler R, Degenhardt C, Kuhn M, Runkel N, Paul M, Hoyer J (2000) 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 87:496–503
Köhler R, Brakemeier S, Kuhn M, Behrens C, Real R, Degenhardt C, Orzechowski HD, Pries AR, Paul M, Hoyer J (2001) Impaired hyperpolarization in regenerated endothelium after balloon catheter injury. Circ Res 89:174–179
Lifton RP, Gharavi AG, Geller DS (2001) Molecular mechanisms of human hypertension. Cell 104:545–556
Liu Y, Sellke EW, Feng J, Clements RT, Sodha NR, Khabbaz KR, Senthilnathan V, Alper SL, Sellke FW (2008) Calcium-activated potassium channels contribute to human skeletal muscle microvascular endothelial dysfunction related to cardiopulmonary bypass. Surgery 144:239–244
Marchenko SM, Sage SO (1996) Calcium-activated potassium channels in the endothelium of intact rat aorta. J Physiol 492(Pt 1):53–60
McCobb DP, Fowler NL, Featherstone T, Lingle CJ, Saito M, Krause JE, Salkoff L (1995) A human calcium-activated potassium channel gene expressed in vascular smooth muscle. Am J Physiol 269:H767–H777
Meredith AL, Thorneloe KS, Werner ME, Nelson MT, Aldrich RW (2004) Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel. J Biol Chem 279:36746–36752
Nelson MT, Cheng H, Rubart M, Santana LF, Bonev AD, Knot HJ, Lederer WJ (1995) Relaxation of arterial smooth muscle by calcium sparks. Science 270:633–637
Nielsen T, Burgdorf KS, Grarup N, Borch-Johnsen K, Hansen T, Jorgensen T, Pedersen O, Andersen G (2008) The KCNMB1 Glu65Lys polymorphism associates with reduced systolic and diastolic blood pressure in the Inter99 study of 5729 Danes. J Hypertens 26:2142–2146
Nilius B, Droogmans G (2001) Ion channels and their functional role in vascular endothelium. Physiol Rev 81:1415–1459
Perez GJ, Bonev AD, Patlak JB, Nelson MT (1999) Functional coupling of ryanodine receptors to KCa channels in smooth muscle cells from rat cerebral arteries. J Gen Physiol 113:229–238
Plüger S, Faulhaber J, Furstenau M, Lohn M, Waldschutz R, Gollasch M, Haller H, Luft FC, Ehmke H, Pongs O (2000) Mice with disrupted BK channel beta1 subunit gene feature abnormal Ca(2+) spark/STOC coupling and elevated blood pressure. Circ Res 87:E53–E60
Ruttiger L, Sausbier M, Zimmermann U, Winter H, Braig C, Engel J, Knirsch M, Arntz C, Langer P, Hirt B, Muller M, Kopschall I, Pfister M, Munkner S, Rohbock K, Pfaff I, Rusch A, Ruth P, Knipper M (2004) Deletion of the Ca2+-activated potassium (BK) alpha-subunit but not the BKbeta1-subunit leads to progressive hearing loss. Proc Natl Acad Sci USA 101:12922–12927
Sausbier M, Hu H, Arntz C, Feil S, Kamm S, Adelsberger H, Sausbier U, Sailer CA, Feil R, Hofmann F, Korth M, Shipston MJ, Knaus HG, Wolfer DP, Pedroarena CM, Storm JF, Ruth P (2004) Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency. Proc Natl Acad Sci USA 101:9474–9478
Sausbier M, Arntz C, Bucurenciu I, Zhao H, Zhou XB, Sausbier U, Feil S, Kamm S, Essin K, Sailer CA, Abdullah U, Krippeit-Drews P, Feil R, Hofmann F, Knaus HG, Kenyon C, Shipston MJ, Storm JF, Neuhuber W, Korth M, Schubert R, Gollasch M, Ruth P (2005) Elevated blood pressure linked to primary hyperaldosteronism and impaired vasodilation in BK channel-deficient mice. Circulation 112:60–68
Schreiber M, Salkoff L (1997) A novel calcium-sensing domain in the BK channel. Biophys J 73:1355–1363
Schubert R, Nelson MT (2001) Protein kinases: tuners of the BKCa channel in smooth muscle. Trends Pharmacol Sci 22:505–212
Seibold MA, Wang B, Eng C, Kumar G, Beckman KB, Sen S, Choudhry S, Meade K, Lenoir M, Watson HG, Thyne S, Williams LK, Kumar R, Weiss KB, Grammer LC, Avila PC, Schleimer RP, Burchard EG, Brenner R (2008) An african-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity. Hum Mol Genet 17:2681–2690
Senti M, Fernandez-Fernandez JM, Tomas M, Vazquez E, Elosua R, Marrugat J, Valverde MA (2005) Protective effect of the KCNMB1 E65K genetic polymorphism against diastolic hypertension in aging women and its relevance to cardiovascular risk. Circ Res 97:1360–1365
Shi J, Krishnamoorthy G, Yang Y, Hu L, Chaturvedi N, Harilal D, Qin J, Cui J (2002) Mechanism of magnesium activation of calcium-activated potassium channels. Nature 418:876–880
Si H, Heyken WT, Wölfle SE, Tysiac M, Schubert R, Grgic I, Vilianovich L, Giebing G, Maier T, Gross V, Bader M, de Wit C, Hoyer J, Köhler R (2006) Impaired endothelium-derived hyperpolarizing factor-mediated dilations and increased blood pressure in mice deficient of the intermediate-conductance Ca2+-activated K+ channel. Circ Res 99:537–544
Sprossmann F, Pankert P, Sausbier U, Wirth A, Zhou XB, Madlung J, Zhao H, Bucurenciu I, Jakob A, Lamkemeyer T, Neuhuber W, Offermanns S, Shipston MJ, Korth M, Nordheim A, Ruth P, Sausbier M (2009) Inducible knockout mutagenesis reveals compensatory mechanisms elicited by constitutive BK channel deficiency in overactive murine bladder. FEBS J 276:1680–1697
Taylor MS, Bonev AD, Gross TP, Eckman DM, Brayden JE, Bond CT, Adelman JP, Nelson MT (2003) Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure. Circ Res 93:124–131
Taylor SG, Weston AH (1988) Endothelium-derived hyperpolarizing factor: a new endogenous inhibitor from the vascular endothelium. Trends Pharmacol Sci 9:272–274
Tomas M, Vazquez E, Fernandez-Fernandez JM, Subirana I, Plata C, Heras M, Vila J, Marrugat J, Valverde MA, Senti M (2008) Genetic variation in the KCNMA1 potassium channel alpha subunit as risk factor for severe essential hypertension and myocardial infarction. J Hypertens 26:2147–2153
Toyama K, Wulff H, Chandy KG, Azam P, Raman G, Saito T, Fujiwara Y, Mattson DL, Das S, Melvin JE, Pratt PF, Hatoum OA, Gutterman DD, Harder DR, Miura H (2008) The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans. J Clin Invest 118(9):3025–3037
Urakami-Harasawa L, Shimokawa H, Nakashima M, Egashira K, Takeshita A (1997) Importance of endothelium-derived hyperpolarizing factor in human arteries. J Clin Invest 100:2793–2799
Van de Voorde J, Vanheel B, Leusen I (1992) Endothelium-dependent relaxation and hyperpolarization in aorta from control and renal hypertensive rats. Circ Res 70:1–8
Waldron GJ, Garland CJ (1994) Effect of potassium channel blockers on L-NAME insensitive relaxations in rat small mesenteric artery. Can J Physiol Pharmacol 72:11
Wei A, Solaro C, Lingle C, Salkoff L (1994) Calcium sensitivity of BK-type KCa channels determined by a separable domain. Neuron 13:671–681
Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S, Wulff H (2005) International union of pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels. Pharmacol Rev 57:463–472
Werner ME, Zvara P, Meredith AL, Aldrich RW, Nelson MT (2005) Erectile dysfunction in mice lacking the large-conductance calcium-activated potassium (BK) channel. J Physiol 567:545–556
Wulff H, Zhorov BS (2008) K+ channel modulators for the treatment of neurological disorders and autoimmune diseases. Chem Rev 108:1744–1773
Xia XM, Zeng X, Lingle CJ (2002) Multiple regulatory sites in large-conductance calcium-activated potassium channels. Nature 418:880–884
Yamaguchi M, Nakayama T, Fu Z, Naganuma T, Sato N, Soma M, Doba N, Hinohara S, Morita A, Mizutani T (2009) Relationship between haplotypes of KCNN4 gene and susceptibility to human vascular diseases in Japanese. Med Sci Monit 15:CR389–CR397
Zygmunt PM, Hogestatt ED (1996) Role of potassium channels in endothelium-dependent relaxation resistant to nitroarginine in the rat hepatic artery. Br J Pharmacol 117:1600–1606
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Köhler, R. Single-nucleotide polymorphisms in vascular Ca2+-activated K+-channel genes and cardiovascular disease. Pflugers Arch - Eur J Physiol 460, 343–351 (2010). https://doi.org/10.1007/s00424-009-0768-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-009-0768-6