Regulation and function of vascular smooth muscle potassium channels

Regulation and function of vascular smooth muscle potassium channels
Regulation and function of vascular smooth muscle potassium channels © Universität Augsburg


We have shown that BK channels are regulated by a number of signaling pathways, by PKG (Robertson et al., 1993;Gribkova et al., 2002), by PKA (Schubert et al., 1996), by PKC (Schubert et al., 1999b;Mladenov et al., 2008) as well as intracellular pH (Petkova-Kirova et al., 2000;Schubert et al., 2001). In small arteries, these signaling pathways mediate the contribution of BK channels to NO- and iloprost-induced dilations (Schubert et al., 1997;Sausbier et al., 2000;Sausbier et al., 2005;Climent et al. 2012;Iozzi et al. 2013), to ghrelin- (Mladenov et al., 2008) and methoxamine-induced vasocontraction, where the latter was shown to increase with postnatal maturation (Shvetsova et al., 2019; Ma et al., 2020) as well as to the setting of the level of myogenic tone (Wesselman et al., 1997;Schubert et al., 1999a; Ma et al., 2020). Interestingly, when the full range of vessel tone was explored, NO-induced dilations were shown to be limited by BK channels, only at high levels of vessel tone BK channels facilitate this dilation (Schmid et al., 2018). All these findings were obtained on different small arteries from rats and PKG- as well as BK channel-deficient mice. Some of these data have been summarized in a review article (Schubert & Nelson, 2001).


Further, we could demonstrate that inwardly rectifying potassium (Kir2) channels are activated by NO, where this effect contributes to the NO-induced dilation of small arteries (Schubert et al., 2004) and that the negative feedback regulation of vasocontraction by Kir2 channels decreases during postnatal maturation (Shvetsova et al., 2019).


Ongoing studies are focused on the biophysical and pharmacological properties of several voltage-operated potassium channels and their function in the cardiovascular system. It was found that Kv7 channels contribute to the vasodilating effect of factors released from periadventitial fat (Schleifenbaum et al., 2010; Zavaritskaya et al., 2013, Tsvetkov et al., 2016), lose their dominating role in the negative feedback regulation of vasocontraction during postnatal maturation (Shvetsova et al., 2019; Ma et al., 2020) and are limited in their role as negative feedback on vasoconstriction by BK channels (Ma et al., 2020). These channels share with BK channels the ability to mediate vasodilation by the novel K channel opener GoSlo (Zavaritskaya et al., 2020). Overviews of the tools to study Kv7 channels and of the role of different K channels in early postnatal maturation have been presented in reviews (Gollasch et al., 2018; Svetsova et al., 2021).


Recently it was shown that another, less well studied class of K channels, TASK-1 channels, also lose their ability to mediate negative feedback regulation on vasocontraction during postnatal maturation (Shvetsova et al., 2020).





Climent, B., Schubert, R., Stankevicius, E., Garcia-Sacristan, A., Simonsen, U., Rivera, L. (2012)  Large conductance Ca2+-activated K+ channels modulate endothelial cell outward currents and nitric oxide release in the intact rat superior mesenteric artery. BBRC 417, 1007-1013


Gollasch, M., Welsh, D.G., Schubert, R. (2018) Perivascular adipose tissue and the dynamic regulation of Kv7 and Kir channels: Implications for resistant hypertension. Microcirculation 25, e12434


Gribkova, I. V., Schubert, R., Serebriakov, V. N. (2002) Study of NO action on calcium-activated potassium channel of the rat artery smooth muscle cells. Ross.Fiziol.Zh.Im I.M.Sechenova 88, 1199-1205


Iozzi, D., Schubert, R., Kalenchuk, V.U., Neri, A., Sgaragli, G., Fusi, F., Saponara, S. (2013) Quercetin relaxes rat tail main artery partly via a PKG-mediated stimulation of KCa1.1 channels. Acta Physiol 208, 329-39 


Ma, D., Gaynullina, D. K., Schmidt, N., Mladenov, M., Schubert, R. (2020) The functional availability of arterial Kv7 channels is suppressed considerably by large-conductance calcium-activated potassium channels in 2- to 3-month old but not in 10- to 15-day old rats. Front Physiol 11, 597395


Mladenov, M. I., Hristov, K. L., Dimitriova, D. Z., Schubert, R., Lubomirov, L. T., Gjorgoski, I. K., Duridanova, D. B., Gagov, H. S. (2008) Ghrelin signalling in guinea-pig femoral artery smooth muscle cells. Acta Physiol 194, 195-206


Petkova-Kirova, P., Gagov, H., Krien, U., Duridanova, D., Noack, T., Schubert, R. (2000) 4-aminopyridine affects rat arterial smooth muscle BK(Ca) currents by changing intracellular pH. Br J Pharmacol 131, 1643-1650


Robertson, B. E., Schubert, R., Hescheler, J., Nelson, M. T. (1993) cGMP-Dependent Protein Kinase Activates Ca-Activated K-Channels in Cerebral Artery Smooth Muscle Cells. Am J Physiol 265, C299-C303


Sausbier, M., Arntz, C., Bucurenciu, I., Zhao, H., Zhou, X. B., Sausbier, U., Feil, S., Kamm, S., Essin, K., Sailer, C. A., Abdullah, U., Krippeit-Drews, P., Feil, R., Hofmann, F., Knaus, H. G., Kenyon, C., Shipston, M. J., Storm, J. F., 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


Sausbier, M., Schubert, R., Voigt, V., Hirneiss, C., Pfeifer, A., Korth, M., Kleppisch, T., Ruth, P., Hofmann, F. (2000) Mechanisms of NO/cGMP-dependent vasorelaxation. Circ Res  87, 825-830


Schleifenbaum, J., Köhn, C., Voblova, N., Dubrovska, G., Zavarirskaya, O., Gloe, T., Crean, C.S., Luft, F.C., Huang, Y., Schubert, R., Gollasch, M. (2010) Systemic peripheral artery relaxation by KCNQ channel openers and hydrogen sulfide. J Hypertens 28, 1875-82


Schmid, J., Müller, B., Heppeler, D., Gaynullina, D., Kassmann, M., Gagov, H., Mladenov, M., Gollasch, M., Schubert, R. (2018) The Unexpected Role of Calcium-Activated Potassium Channels: Limitation of NO-Induced Arterial Relaxation. J Am Heart Assoc 7, e007808


Schubert, R., Krien, U., Gagov, H. (2001) Protons inhibit the BK(Ca) channel of rat small artery smooth muscle cells. J Vasc Res 38, 30-38


Schubert, R., Krien, U., Wulfsen, I., Schiemann, D., Lehmann, G., Ulfig, N., Veh, R. W., Schwarz, J. R., Gagov, H. (2004) Nitric oxide donor sodium nitroprusside dilates rat small arteries by activation of inward rectifier potassium channels. Hypertension 43, 891-896


Schubert, R., Lehmann, G., Serebryakov, V. N., Mewes, H., Hopp, H.-H. (1999a) cAMP-dependent protein kinase is in an active state in rat small arteries possessing a myogenic tone. Am J Physiol  277, H1145-H1155


Schubert, R. Nelson, M. T. (2001) Protein kinases: tuners of the BKCa channel in smooth muscle. Trends Pharmacol Sci 22, 505-512


Schubert, R., Noack, T., Serebryakov, V. N. (1999b) Protein kinase C reduces the KCa current of rat tail artery smooth muscle cells. Am J Physiol  276, C648-C658


Schubert, R., Serebryakov, V. N., Engel, H., Hopp, H.-H. (1996) Iloprost activates KCa channels of vascular smooth muscle cells: role of cAMP-dependent protein kinase. Am J Physiol 271, C1203-C1211


Schubert, R., Serebryakov, V. N., Mewes, H., Hopp, H.-H. (1997) Iloprost dilates rat small arteries: role of KATP- and KCa-channel activation by cAMP-dependent protein kinase. Am J Physiol 272, H1147-H1156


Shvetsova, A. A., Gaynullina, D. K., Tarasova, O. S., Schubert, R. (2019) Negative feedback regulation of vasocontraction by potassium channels in 10-to 15-day-old rats: Dominating role of K(v)7 channels Acta Physiol 225, e13176


Shvetsova, A., Gaynullina, D. K., Schmidt, N., Bugert, P., Lukoshkova, E. V., Tarasova, O. S., Schubert, R. (2020) TASK‐1 channel blockade by AVE1231 increases vasocontractile responses and BP in 1‐ to 2‐week‐old but not adult rats. Br J Pharmacol 177,c5148-5162


Shvetsova, A. A., Gaynullina, D. K., Tarasova, O. S., Schubert,R. (2021) Remodeling of arterial tone regulation in postnatal development: focus on smooth muscle cell potassium channels. International Journal of Molecular Sciences 22, 5413


Tsvetkov, D., Tano, J. Y., Kassmann, M., Wang, N., Schubert, R., Gollasch, M. (2016) The Role of DPO-1 and XE991-Sensitive Potassium Channels in Perivascular Adipose Tissue-Mediated Regulation of Vascular Tone. Front Physiol 7, 335


Wesselman, J. P. M., Schubert, R., VanBavel, E., Nilsson, H., Mulvany, M. J. (1997) KCa-channel blockade prevents sustained pressure-induced depolarization in rat mesenteric small arteries. Am J Physiol 272, H2241-H2249


Zavaritskaya, O., Zhuravleva, N., Schleifenbaum, J., Gloe, T., Devermann, L., Kluge, R., Mladenov, M., Frey, M., Gagov, H., Fésüs, G., Gollasch, M., Schubert, R. (2013) Role of KCNQ Channels in Skeletal Muscle Arteries and Periadventitial Vascular Dysfunction. Hypertension 61, 151-59


Zavaritskaya, O., Dudem, S., Ma, D., Rabab, K. E., Albrecht, S., Tsvetkov, D., Kassmann, M., Thornbury, K., Mladenov, M., Kammermeier, C., Sergeant, G., Mullins, N., Wouappi, O., Wurm, H., Kannt, A., Gollasch, M., Hollywood, M. A., Schubert, R. (2020) Vasodilation of rat skeletal muscle arteries by the novel BK channel opener GoSlo is mediated by the simultaneous activation of BK and Kv7 channels. Br J Pharmacol 177, 1164-1186