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Lab Schubert

Regulation and function of vascular smooth muscle potassium channels

We have shown that BK channels are regulated by a number of signalling 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 the intracellular pH (Petkova-Kirova et al., 2000;Schubert et al., 2001). In small arteries, these signalling pathways mediate the contribution of BK channels to NO- and iloprost-induced dilations (Climent et al. 2012;Iozzi et al. 2013;Sausbier et al., 2000;Sausbier et al., 2005;Schubert et al., 1997), to ghrelin-induced contractions (Mladenov et al., 2008) as well as to the setting of the level of the myogenic tone (Wesselman et al., 1997;Schubert et al., 1999a). 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).

Regulation and function of vascular smooth muscle potassium channels

Further, we could demonstrate that inwardly rectifying potassium channels are activated by NO and that this effect contributes to the NO-induced dilation of small arteries (Schubert et al., 2004).

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).

References

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.

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.

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 (Oxf) 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.

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.

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.

Functional remodeling of vascular smooth muscle during early postnatal development

Our studies showed that the signaling mechanisms governing vascular tone regulation possess a high degree of plasticity. Thus, with maturation the anticontractile effect of the endothelium decreases (Gaynullina et al. 2013), sympathetic nerves reduce arterial smooth muscle Ca2+-sensitivity (Puzdrova et al. 2014) and mRNA and miRNA expression changes in a correlated manner (Gaynullina et al. 2015).

References

Gaynullina, D., Dweep, H., Gloe, T., Tarasova, O.S., Sticht, C., Gretz, N., Schubert, R. (2015). Alteration of mRNA and microRNA expression profiles in rat muscular type vasculature in early postnatal development. Sci Rep. 5, 11106 doi: 10.1038/srep11106

Gaynullina, D., Lubomirov, L.T., Sofronova, S.I., Kalenchuk, V.U., Gloe, T., Pfitzer, G., Tarasova, O.S., Schubert, R. (2013). Functional remodelling of arterial endothelium during early postnatal development in rats. Cardiovasc. Res. 99, 612-21.

Puzdrova, V.A., Kudryashova, T.V., Gaynullina, D.K., Mochalov, S.V., Aalkjaer, C., Nilsson, H., Vorotnikov, A.V., Schubert, R., Tarasova, O.S. (2014). Trophic action of sympathetic nerves reduces arterial smooth muscle Ca2+-sensitivity during early postnatal development in rats. Acta.Physiol. 212, 128-141.

Mechanotransduction mechanisms in vascular smooth muscle cells

We could demonstrate that PKA (Schubert et al., 1999), Rho-kinase (Schubert et al., 2002) and BK channels (Sausbier et al., 2005) contribute to the setting of the level of small artery myogenic tone. In addition, it was demonstrated that the myogenic response is mediated by Rho-kinase (Schubert et al., 2002) and modulated by neuronal influences (Anschutz & Schubert, 2005). The mechanisms of the myogenic response have been discussed in 4 review articles (Schubert & Mulvany, 1999;Schubert & Brayden, 2005;Schubert et al., 2008;Lidington et al. 2013).

Mechanotransduction mechanisms in vascular smooth muscle cells

We have been participating in a cooperative study showing that endothelial TRPV4 channels are involved in flow-induced vessel dilations (Kohler et al., 2006).

References

Anschutz, S. Schubert, R. (2005). Modulation of the myogenic response by neurogenic influences in rat small arteries. Br.J.Pharmacol. 146, 226-233.

Kohler, R., Heyken, W. T., Heinau, P., Schubert, R., Si, H., Kacik, M., Busch, C., Grgic, I., Maier, T., Hoyer, J. (2006). Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation. Arterioscler.Thromb.Vasc.Biol. 26, 1495-1502.

Lidington, D., Schubert, R., Bolz, S.S. (2013). Capitalizing on diversity: an integrative approach towards the multiplicity of cellular mechanisms underlying myogenic responsiveness. Cardiovasc. Res. 97, 404-12.

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.

Schubert, R. Brayden, J. E. (2005). Stretch-activated cation channels and the myogenic response of small arteries. In Mechanosensitivity in Cells and Tissues pp. 402-417.

Schubert, R., Kalentchuk, V. U., Krien, U. (2002). Rho kinase inhibition partly weakens myogenic reactivity in rat small arteries by changing calcium sensitivity. Am.J.Physiol Heart Circ.Physiol 283, H2288-H2295.

Schubert, R., Lehmann, G., Serebryakov, V. N., Mewes, H., Hopp, H.-H. (1999). 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., Lidington, D., Bolz, S. S. (2008). The emerging role of Ca2+ sensitivity regulation in promoting myogenic vasoconstriction. Cardiovasc.Res. 77, 8-18.

Schubert, R. Mulvany, M. J. (1999). The myogenic response: established facts and attractive hypotheses. Clin.Sci. 96, 313-326.

Mechanisms of calcium sensitivity regulation

In our experiments we have demonstrated that Rho-kinase is contributing to the myogenic response by increasing the calcium sensitivity of the contractile apparatus (Schubert et al., 2002).

In addition, we have shown that the dilation induced by urocortin is caused by a PKA-mediated alteration of the calcium sensitivity (Lubomirov et al., 2001), associated with a dephosphorylation of MYPT1 and an activation of MLCP (Lubomirov et al., 2006a;Lubomirov et al., 2006b;Pfitzer et al., 2006).

Mechanisms of calcium sensitivity regulation

Our data further demonstrates that sympathetic nerves reduce arterial smooth muscle Ca2+-sensitivity during postnatal development (Puzdrova et al. 2014).

We have been participating in a cooperative study showing that adenosine is increasing the calcium sensitivity of the contractile apparatus via p38 MAP-kinase (Martinka et al., 2008).

References

Lubomirov, L., Gagov, H., Petkova-Kirova, P., Duridanova, D., Kalentchuk, V. U., Schubert, R. (2001). Urocortin relaxes rat tail arteries by a PKA-mediated reduction of the sensitivity of the contractile apparatus for calcium. Br.J.Pharmacol. 134, 1564-1570.

Lubomirov, L. T., Reimann, K., Metzler, D., Hasse, V., Stehle, R., Ito, M., Hartshorne, D. J., Gagov, H., Pfitzer, G., Schubert, R. (2006a). Urocortin-induced decrease in Ca2+ sensitivity of contraction in mouse tail arteries is attributable to cAMP-dependent dephosphorylation of MYPT1 and activation of myosin light chain phosphatase. Circ.Res. 98, 1159-1167.

Lubomirov, L. T., Schubert, R., Gagov, H. S., Duridanova, D. B., Pfitzer, G. (2006b). [Urocortin decreases phosphorylation of MYPT1 and increases the myosin phosphatase activity via elevation of the intracellular level of cAMP]. Biofizika 51, 773-780.

Martinka, P., Lai, E. Y., Fahling, M., Jankowski, V., Jankowski, J., Schubert, R., Gaestel, M., Persson, A. E., Persson, P. B., Patzak, A. (2008). Adenosine increases calcium sensitivity via receptor-independent activation of the p38/MK2 pathway in mesenteric arteries. Acta Physiol (Oxf) 193, 37-46.

Pfitzer, G., Lubomirov, L. T., Reimann, K., Gagov, H., Schubert, R. (2006). Regulation of the crossbridge cycle in vascular smooth muscle by cAMP signalling. J.Muscle Res.Cell Motil. 27, 445-454.

Puzdrova, V.A., Kudryashova, T.V., Gaynullina, D.K., Mochalov, S.V., Aalkjaer, C., Nilsson, H., Vorotnikov, A.V., Schubert, R., Tarasova, O.S. (2014). Trophic action of sympathetic nerves reduces arterial smooth muscle Ca2+-sensitivity during early postnatal development in rats. Acta.Physiol. 212, 128-141

Schubert, R., Kalentchuk, V. U., Krien, U. (2002). Rho kinase inhibition partly weakens myogenic reactivity in rat small arteries by changing calcium sensitivity. Am.J.Physiol Heart Circ.Physiol 283, H2288-H2295.

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