TASK-1 channels: functional role in arterial smooth muscle cells

A change in the diameter of small arteries and arterioles is a key mechanism for the regulation vascular bed resistance and, consequently, blood pressure and blood flow in organs and tissues. The tone of arterial smooth muscle cells (SMC) depends on the level of membrane potential (MP), which, in turn, is determined by the balance of depolarizing and hyperpolarizing ion currents. The main hyperpolarizing current of SMC is the outward potassium current. Activation and opening of potassium channels counteract depolarization, inhibit calcium entry into the cell and contraction. Thus, potassium channels play an anticontractile role in the arteries. TASK-1 channels, members of two-pore potassium channel family (K2P), have been described relatively recently in the vasculature. It is known that TASK-1 channels mediate outward potassium leakage current in arterial SMC. In addition, TASK-1 channels are regulated by a number of stimuli: their activity augments with an increase of extracellular pH, decreases at hypoxia, and can also change under the influence of inhalational/local anesthetics and vasoactive substances. TASK-1 channels play an important role in the regulation of arterial tone in pulmonary circulation, their dysfunction is one of the causes of arterial pulmonary hypertension development. In systemic arteries of adult animals, the influence of TASK-1 channels under normal pH is small or absent, but it can manifest itself under conditions of extracellular alkalosis. In addition, the anticontractile role of TASK-1 channels is more pronounced at the early period of postnatal development. This review outlines the current understanding of the functional role and regulation of TASK-1 channels in the vascular system.

1. Tykocki N.R., Boerman E.M., Jackson W.F. Smooth muscle ion channels and regulation of vascular tone in resistance arteries and arterioles // Compr. Physiol. 2017. Vol. 7. N 2. P. 485–581.

2. Gurney A., Manoury B. Two-pore potassium channels in the cardiovascular system // Eur. Biophys. J. 2009. Vol. 38. N 3. P. 305–318.

3. Shvetsova A.A., Gaynullina D.K., Schmidt N., Bugert P., Lukoshkova E.V, Tarasova O.S., Schubert R. TASK-1 channel blockade by AVE1231 increases vasocontractile responses and BP in 1- to 2-week-old but not adult rats // Br. J. Pharmacol. 2020. Vol. 177. N 22. P. 5148–5162.

4. Lloyd E.E., Marrelli S.P., Bryan R.M. cGMP does not activate two-pore domain K+ channels in cerebrovascular smooth muscle // Am. J. Physiol. – Heart Circ. Physiol. 2009. Vol. 296. № 6. P. 1774–1780.

5. Antigny F., Hautefort A., Meloche J., et al. Potassium channel subfamily K member 3 (KCNK3) contributes to the development of pulmonary arterial hypertension // Circulation. 2016. Vol. 133. N 14. P. 1371–1385.

6. Gardener M.J., Johnson I.T., Burnham M.P., Edward G., Heagerty A.M., Weston A.H. Functional evidence of a role for two-pore domain potassium channels in rat mesenteric and pulmonary arteries // Br. J. Pharmacol. 2004. Vol. 142. N 1. P. 192–202.

7. Ma L., Roman-Campos D., Austin E.D., et al. A novel channelopathy in pulmonary arterial hypertension // N. Engl. J. Med. 2013. Vol. 369. N 4. P. 351–361.

8. Navas Tejedor P., Tenorio Castaño J., Palomino Doza J., Arias Lajara P., Gordo Trujillo G., López Meseguer M., Román Broto A., Lapunzina Abadía P., Escribano Subía P. An homozygous mutation in KCNK3 is associated with an aggressive form of hereditary pulmonary arterial hypertension // Clin. Genet. 2017. Vol. 91. N 3. P. 453–457.

9. Zhang H.S., Liu Q., Piao C.M., Zhu Y., Li Q.Q., Du J., Gu H. Genotypes and phenotypes of Chinese pediatric patients with idiopathic and heritable pulmonary arterial hypertension – a single-center study // Can. J. Cardiol. 2019. Vol. 35. N 12. P. 1851–1856.

10. Haarman M.G., Kerstjens-Frederikse W.S., VissiaKazemier T.R., Breeman K.T.N., Timens W., Vos Y.J., Roofthooft M.T.R., Hillege H.L., Berger R.M.F. The genetic epidemiology of pediatric pulmonary arterial hypertension // J. Pediatr. 2020. Vol. 225. P. 65–73.e5.

11. Cox R.H., Fromme S. Functional expression profile of voltage-gated K+ channel subunits in rat small mesenteric arteries // Cell Biochem. Biophys. 2016. Vol. 74. N 2. P. 263–276.

12. Mackie A.R., Byron K.L. Cardiovascular KCNQ (Kv7) potassium channels: physiological regulators and new targets for therapeutic intervention // Mol. Pharmacol. 2008. Vol. 74. N 5. P. 1171–1179.

13. Cui J., Yang H., Lee U.S. Molecular mechanisms of BK channel activation // Cell. Mol. Life Sci. 2009. Vol. 66. N 5. P. 852–875.

14. Bi D., Toyama K., Lemaitre V., Takai J., Fan F., Jenkins D.P., Wulff H., Gutterman D.D., Park F., Miura H. The intermediate conductance calcium-activated potassium channel KCa3.1 regulates vascular smooth muscle cell proliferation via controlling calcium-dependent signaling // J. Biol. Chem. 2013. Vol. 288. N 22. P. 15843–15853.

15. Tharp D.L., Wamhoff B.R., Turk J.R., Bowles D.K. Upregulation of intermediate-conductance Ca2+-activated K+ channel (IKCa1) mediates phenotypic modulation of coronary smooth muscle // Am. J. Physiol. – Heart Circ. Physiol. 2006. Vol. 291. N 5. P. H2493–H2503.

16. Gebremedhin D., Kaldunski M., Jacobs E.R., Harder D.R., Roman R.J. Coexistence of two types of Ca2+- activated K+ channels in rat renal arterioles // Am. J. Physiol. 1996. Vol. 270. N 1. P. 69–81.

17. Sun W.T., Hou H.T., Chen H.X., Xue H.M., Wang J., He G.W., Yang Q. Calcium-activated potassium channel family in coronary artery bypass grafts // J. Thorac. Cardiovasc. Surg. 2021. Vol. 161. N 5. P. e399–e409.

18. Ledoux J., Werner M.E., Brayden J.E., Nelson M.T. Calcium-activated potassium channels and the regulation of vascular tone // Physiology. 2006. Vol. 21. N 1. P. 69–78.

19. Schubert R., Wesselman J.P.M., Nilsson H., Mulvany M.J. Noradrenaline-induced depolarization is smaller in isobaric compared to isometric preparations of rat mesenteric small arteries // Pflügers Arch. Eur. J. Physiol. 1996. Vol. 431. N 5. P. 794–796.

20. Shvetsova A.A., Gaynullina D.K., Tarasova O.S., Schubert R. Negative feedback regulation of vasocontraction by potassium channels in 10- to 15-day-old rats: Dominating role of Kv7 channels // Acta Physiol. 2019. Vol. 225. N 2: e13176.

21. Matsuda H., Saigusa A., Irisawa H. Ohmic conductance through the inwardly rectifying K channel and blocking by internal Mg2+ // Nature. 1987. Vol. 325. N 6100. P. 156–159.

22. Lopatin A.N., Makhina E.N., Nichols C.G. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification // Nature. 1994. Vol. 372. N 6504. P. 366–369.

23. Filosa J.A., Bonev A.D., Straub S.V., Meredith A.L., Wilkerson M.K., Aldrich R.W., Nelson M.T. Local potassium signaling couples neuronal activity to vasodilation in the brain // Nat. Neurosci. 2006. Vol. 9. N 11. P. 1397–1403.

24. Foster M.N., Coetzee W.A. KATP channels in the cardiovascular system // Physiol. Rev. 2016. Vol. 96. N 1. P. 177–252.

25. Tinker A., Aziz Q., Li Y., Specterman M. ATP-sensitive potassium channels and their physiological and pathophysiological roles // Compr. Physiol. 2018. Vol. 8. N 4. P. 1463–1511.

26. Tucker S.J., Gribble F.M., Zhao C., Trapp S., Ashcroft F.M. Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor // Nature. 1997. Vol. 387. N 6629. P. 179–183.

27. Ammalia C., Moorhouse A., Gribble F., Ashfield R., Proks P., Smith P.A., Sakura H., Coles B., Ashcroft S.L.H., Ashcroft F.M. Promiscuous coupling between the sulphonylurea receptor and inwardly rectifying potassium channels // Nature. 1996. Vol. 379. N 6565. P. 545–548.

28. Gurney A.M., Osipenko O.N., MacMillan D., McFarlane K.M., Tate R.J., Kempsill F.E.J. Two-pore domain K channel, TASK-1, in pulmonary artery smooth muscle cells // Circ. Res. 2003. Vol. 93. N 10. P. 957–964.

29. Goldstein S.A.N., Bockenhauer D., O’Kelly I., Zilberberg N. Potassium leak channels and the KCNK family of two-p-domain subunits // Nat. Rev. Neurosci. 2001. Vol. 2. N 3. P. 175–184.

30. Gardener M.J., Johnson I.T., Burnham M.P., Edward, G., Heagerty A.M., Weston A.H. Functional evidence of a role for two-pore domain potassium channels in rat mesenteric and pulmonary arteries // Br. J. Pharmacol. 2004. Vol. 142. N 1. P. 192–202.

31. Lopes C.M.B., Gallagher P.G., Buck M.E., Butler M.H., Goldstein S.A.N. Proton block and voltage gating are potassium-dependent in the cardiac leak channel Kcnk3 // J. Biol. Chem. 2000. Vol. 275. N 22. P. 16969–16978.

32. Duprat F., Lesage F., Fink M., Reyes R., Heurteaux C., Lazdunski M. TASK, a human background K+ channel to sense external pH variations near physiological pH // EMBO J. 1997. Vol. 16. N 17. P. 5464–5471.

33. Olschewski A., Li Y., Tang B., Hanze J., Eul B., Bohle R.M., Wilhelm J., Morty R.E., Brau M.E., Weir E.K., Kwapiszewska G., Klepetko W., Seeger W., Olschewski H. Impact of TASK-1 in human pulmonary artery smooth muscle cells // Circ. Res. 2006. Vol. 98. N 8. P. 1072–1080.

34. Yuill K., Ashmole I., Stanfield P.R. The selectivity filter of the tandem pore potassium channel TASK-1 and its pH-sensitivity and ionic selectivity // Pflugers Arch. Eur. J. Physiol. 2004. Vol. 448. N 1. P. 63–69.

35. Morton M.J., O’Connell A.D., Sivaprasadarao A., Hunter M. Determinants of pH sensing in the two-pore domain K+ channels TASK-1 and -2 // Pflügers Arch. – Eur. J. Physiol. 2003. Vol. 445. N 5. P. 577–583.

36. Bao L., Cox D.H. Gating and ionic currents reveal how the BKCa channel’s Ca2+ sensitivity is enhanced by its β1 subunit // J. Gen. Physiol. 2005. Vol. 126. N 4. P. 393–412.

37. Jepps T.A., Carr G., Lundegaard P.R., Olesen S.-P., Greenwood I.A. Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone // J. Physiol. 2015. Vol. 593. N 24. P. 5325–5340.

38. O’Kelly I., Goldstein S.A.N. Forward transport of K2P3.1: mediation by 14-3-3 and COPI, modulation by p11 // Traffic. 2008. Vol. 9. N 1. P. 72–78.

39. Renigunta V., Fischer T., Zuzarte M., Kling S., Zou X., Siebert K., Limberg M.M., Rinné S., Decher N., Schlichthörl G., Daut J. Cooperative endocytosis of the endosomal SNARE protein syntaxin-8 and the potassium channel TASK-1 // Mol. Biol. Cell. 2014. Vol. 25. N 12. P. 1877–1891.

40. Kiyoshi H., Yamazaki D., Ohya S., Kitsukawa M., Muraki K., Saito S., Ohizumi Y., Imaizumi Y. Molecular and electrophysiological characteristics of K+ conductance sensitive to acidic pH in aortic smooth muscle cells of WKY and SHR // Am. J. Physiol. – Heart Circ. Physiol. 2006. Vol. 291. N 6. P. H2723–H2734.

41. White R., Ho W.S.V., Bottrill F.E., Ford W.R., Hiley C.R. Mechanisms of anandamide-induced vasorelaxation in rat isolated coronary arteries // Br. J. Pharmacol. 2001. Vol. 134. N 4. P. 921–929.

42. Van den Bossche I., Vanheel B. Influence of cannabinoids on the delayed rectifier in freshly dissociated smooth muscle cells of the rat aorta // Br. J. Pharmacol. 2000. Vol. 131. N 1. P. 85–93.

43. Martín P., Enrique N., Palomo A.R.R., Rebolledo A., Milesi V. Bupivacaine inhibits large conductance, voltage- and Ca2+- activated K+ channels in human umbilical artery smooth muscle cells // Channels. 2012. Vol. 6. N 3. P. 174–180.

44. Patel A.J., Honoré E., Lesage, F., Fink M., Romey G., Lazdunski M. Inhalational anesthetics activate two-poredomain background K+ channels // Nat. Neurosci. 1999. Vol. 2. N 5. P. 422–426.

45. Buljubasic N., Rusch N.J., Marijic J., Kampine J.P., Bosnjak Z.J. Effects of halothane and isoflurane on calcium and potassium channel currents in canine coronary arterial cells // Anesthesiology. 1992. Vol. 76. N 6. P. 990–998.

46. Kiper A.K., Rinné S., Rolfes C., Ramírez D., Seebohm G., Netter M.F., González W., Decher N. Kv1.5 blockers preferentially inhibit TASK-1 channels: TASK-1 as a target against atrial fibrillation and obstructive sleep apnea? // Pflugers Arch. Eur. J. Physiol. 2015. Vol. 467. N 5. P. 1081–1090.

47. Wirth K.J., Brendel J., Steinmeyer K., Linz D.K., Rütten H., Gögelein H. In vitro and in vivo effects of the atrial selective antiarrhythmic compound AVE1231 // J. Cardiovasc. Pharmacol. 2007. Vol. 49. N 4. P. 197–206.

48. Ehrlich J.R., Ocholla H., Ziemek D., Rütten H., Hohnloser S.H., Gögelein H. Characterization of human cardiac Kv1.5 inhibition by the novel atrial-selective antiarrhythmic compound AVE1231 // J. Cardiovasc. Pharmacol. 2008. Vol. 51. N 4. P. 380–387.

49. Lambert M., Capuano V., Boet A., et al. Characterization of Kcnk3-mutated rat, a novel model of pulmonary hypertension // Circ. Res. 2019. Vol. 125. N 7. P. 678–695.

50. Yamaguchi K., Takasugi T., Fujita H., Mori M., Oyamada Y., Suzuki K., Miyata A., Aoki T., Suzuki Y. Endothelial modulation of pH-dependent pressor response in isolated perfused rabbit lungs // Am. J. Physiol. – Heart Circ. Physiol. 1996. Vol. 270. N 39. P. 252–258.

51. Balasubramanyan N., Halla T.R., Ghanayem N.S., Gordon J.B. Endothelium-independent and -dependent vasodilation in alkalotic and acidotic piglet lungs // Pediatr. Pulmonol. 2000. Vol. 30. N 3. P. 241–248.

52. Post J.M., Hume J.R., Archer S.L., Weir E.K. Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction // Am. J. Physiol. 1992. Vol. 262. N 4. P. C882–C890.

53. Nagaraj C., Tang B., Bálint Z., Wygrecka M., Hrzenjak A., Kwapiszewska G., Stacher E., Lindenmann J., Weir E.K., Olschewski H., Olschewski A. Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries // Eur. Respir. J. 2013. Vol. 41. N 1. P. 85–95.

54. Mackay C.E., Knock G.A. Control of vascular smooth muscle function by Src-family kinases and reactive oxygen species in health and disease // J. Physiol. 2015. Vol. 593. N 17. P. 3815–3828.

55. Wu W., Platoshyn O., Firth A.L., Yuan J.X.J. Hypoxia divergently regulates production of reactive oxygen species in human pulmonary and coronary artery smooth muscle cells // Am. J. Physiol. – Lung Cell. Mol. Physiol. 2007. Vol. 293. N 4. P. 952–959.

56. Manoury B., Lamalle C., Oliveira R., Reid J., Gurney A.M. Contractile and electrophysiological properties of pulmonary artery smooth muscle are not altered in TASK-1 knockout mice // J. Physiol. 2011. Vol. 589. N 13. P. 3231–3246.

57. Murtaza G., Mermer P., Goldenberg A., Pfeil U., Paddenberg R., Weissmann N., Lochnit G., Kummer W. TASK-1 potassium channel is not critically involved in mediating hypoxic pulmonary vasoconstriction of murine intra-pulmonary arteries // PLoS One. 2017. Vol. 12. N 3: e0174071.

58. Pandit L.M., Lloyd E.E., Reynolds J.O., Lawrence W.S., Reynolds C., Wehrens X.H.T., Bryan R.M. TWIK-2 channel deficiency leads to pulmonary hypertension through a rho-kinase-mediated process // Hypertension. 2014. Vol. 64. N 6. P. 1260–1265.

59. Wiedmann F., Beyersdorf C., Zhou X.B., Kraft M., Foerster K.I., El-Battrawy I., Lang S., Borggrefe M., Haefeli W.E., Frey N., Schmidt C. The experimental TASK-1 potassium channel inhibitor A293 can be employed for rhythm control of persistent atrial fibrillation in a translational large animal model // Front. Physiol. 2021. Vol. 11: 629421.

60. Lazarenko V., Shvetsova, A., Gaynullina, D., Schubert R. P.35 TASK-1 channels play an anticontractile role in rat septal coronary artery under pharmacological blockade of endothelium // Artery Res. 2020. Vol. 26. P. S58.

61. Shvetsova A.A., Gaynullina D.K., Tarasova O.S., Schubert R. Remodeling of arterial tone regulation in postnatal development: focus on smooth muscle cell potassium channels // Int. J. Mol. Sci. 2021. Vol. 22. N 11: 5413.

62. Shvetsova A., Lazarenko V., Gaynullina D., Tarasova O., Schubert R. TASK-1 channels emerge as contributors to tone regulation in renal arteries at alkaline pH // Front. Physiol. 2022. Vol. 13: 895863.

63. Lockett M.F. Effects of changes in pO2 and pCO2 and pH on the total vascular resistance of perfused cat kidneys // J. Physiol. 1967. Vol. 193. N 3. P. 671–678.

64. Giaid A., Yanagisawa M., Langleben D., Michel R.P., Levy R., Shennib H., Kimura S., Masaki T., Duguid W.P., Stewart D.J. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension // N. Engl. J. Med. 1993. Vol. 328. N 24. P. 1732–1739.

65. Tang B., Li Y., Nagaraj C., Morty R.E., Gabor S., Stacher E., Voswinckel R., Weissmann N., Leithner K., Olschewski H., Olschewski A. Endothelin-1 inhibits background two-pore domain channel TASK-1 in primary human pulmonary artery smooth muscle cells // Am. J. Respir. Cell Mol. Biol. 2009. Vol. 41. N 4. P. 476–483.

66. Schiekel J., Lindner M., Hetzel A., Wemhöner K., Renigunta V., Schlichthörl G., Decher N., Oliver D., Daut J. The inhibition of the potassium channel TASK-1 in rat cardiac muscle by endothelin-1 is mediated by phospholipase C // Cardiovasc. Res. 2013. Vol. 97. N 1. P. 97–105.

67. Lopes C.M.B., Rohács T., Czirják G., Balla T., Enyedi P., Logothetis D.E. PIP2 hydrolysis underlies agonist-induced inhibition and regulates voltage gating of two-pore domain K+ channels // J. Physiol. 2005. Vol. 564. N 1. P. 117–129.

68. Czirják G., Petheo G.L., Spät A., Enyedi P. Inhibition of TASK-1 potassium channel by phospholipase C // Am. J. Physiol. – Cell Physiol. 2001. Vol. 281. N 2. P. 700–708.

69. Gabriel L., Lvov A., Orthodoxou D., Rittenhouse A.R., Kobertz W.R., Melikian H.E. The acid-sensitive, anestheticactivated potassium leak channel, KCNK3, is regulated by 14-3-3β-dependent, protein kinase C (PKC)-mediated endocytic trafficking // J. Biol. Chem. 2012. Vol. 287. N 39. P. 32354–32366.

70. Matsuoka H., Harada K., Mashima K., Inoue M. Muscarinic receptor stimulation induces TASK1 channel endocytosis through a PKC-Pyk2-Src pathway in PC12 cells // Cell. Signal. 2020. Vol. 65: 109434.

71. Seyler C., Duthil-Straub E., Zitron E., Gierten J., Scholz E.P., Fink R.H.A., Karle C.A., Becker R., Katus H.A., Thomas D. TASK1 (K2P3.1) K+ channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation // Br. J. Pharmacol. 2012. Vol. 165. N 5. P. 1467–1475.

72. Lincoln T.M., Dey N.B., Boerth N.J., Cornwell T.L., Soff G.A. Nitric oxide – cyclic GMP pathway regulates vascular smooth muscle cell phenotypic modulation: Implications in vascular diseases // Acta Physiologica Scandinavica. 1998. Vol. 164. N 4. P. 507–515.

73. Zhou F., Rao F., Deng Y.Q., Yang H., Kuang S.J., Wu F.L., Wu S.L., Xue Y.M., Wu X.M., Deng C.Y. Atorvastatin ameliorates the contractile dysfunction of the aorta induced by organ culture // Naunyn. Schmiedebergs. Arch. Pharmacol. 2019. Vol. 392. N 1. P. 19–28.

74. Puzdrova V.A., Kudryashova T.V., Gaynullina D.K., Mochalov S.V., Aalkjaer C., Nilsson H., Vorotnikov A.V., Schubert R., Tarasova O.S. Trophic action of sympathetic nerves reduces arterial smooth muscle Ca2+ sensitivity during early post-natal development in rats // Acta Physiol. 2014. Vol. 212. N 2. P. 128–141.

75. Mochalov S.V., Tarasova N.V., Kudryashova T.V., Gaynullina D.K., Kalenchuk V.U., Borovik A.S., Vorotnikov A.V., Tarasova O.S., Schubert R. Higher Ca2+-sensitivity of arterial contraction in 1-week-old rats is due to a greater Rho-kinase activity // Acta Physiol. 2018. Vol. 12. N 10: e13044.

76. Hayoz S., Bychkov R., Serir K., Docquier M., Bény J.L. Purinergic activation of a leak potassium current in freshly dissociated myocytes from mouse thoracic aorta // Acta Physiol. 2009. Vol. 195. N 2. P. 247–258.

77. Borkowski K.R., Gros R., Schneider H. Vascular β-adrenoceptor-mediated responses in hypertension and ageing in rats // J. Auton. Pharmacol. 1992. Vol. 12. N 6. P. 389–455.

78. Bieger D., Parai K., Ford C.A., Tabrizchi R. β-Adrenoceptor mediated responses in rat pulmonary artery: Putative role of TASK-1 related K channels // Naunyn. Schmiedebergs. Arch. Pharmacol. 2006. Vol. 373. N 3. P. 186–196.

79. Гайнуллина Д.К., Кирюхина О.О., Тарасова О.С. Оксид азота в эндотелии сосудов: регуляция продукции и механизмы действия // Усп. физиол. наук. 2013. Т. 44. № 4. P. 88–102.

80. Cunningham K.P., Holden R.G., EscribanoSubias P.M., Cogolludo A., Veale E.L., Mathie A. Characterization and regulation of wild-type and mutant TASK-1 two pore domain potassium channels indicated in pulmonary arterial hypertension // J. Physiol. 2019. Vol. 597. N 4. P. 1087–1101.