Mechanisms of calcium sensitivity regulation

Scheme: Calcium measurement in intact vessels. 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. J.Muscle Res.Cell Motil

 

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). Additionally, it was shown that Rho-kinase-mediated calcium sensitivity decreases with maturation (Mochalov et al., 2018). Our data further demonstrate that sympathetic nerves reduce arterial smooth muscle Ca2+-sensitivity during postnatal development (Puzdrova et al., 2014).

 

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

 

Of note, for Src kinase, also known to affect calcium sensitivity, we discovered a major role in calcium-dependent pathways of contractility regulation (Zavaritskaya et al., 2017) suggesting that kinases have the potential to differentially affect calcium-sensitivity as well as calcium-dependent pathways.

 

We have been participating in cooperative studies showing that adenosine is increasing the calcium sensitivity of the contractile apparatus via p38 MAP-kinase (Martinka et al., 2008) and that expression of a leucine zipper positive splice variant of MYPT1 results in a higher NO/cGMP/PKG sensitivity of cerebral arteries (Lubomirov et al., 2018).

 

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., Papadopoulos, S., Filipova, D., Baransi, S., Todorović, D., Lake, P., Metzler, D., Hilsdorf, S., Schubert, R., Schroeter, M. M., Pfitzer, G. (2018) The involvement of phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and MYPT1 isoform expression in NO/cGMP mediated differential vasoregulation of cerebral      arteries compared to systemic arteries. Acta Physiol 224, e13079

 

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 193, 37-46

 

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. (2018) Higher Ca2+-sensitivity of arterial contraction in 1-week-old rats is due to a greater Rho-kinase activity. Acta Physiol 223, e13044

 

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

 

Zavaritskaya, O., Lubomirov, L. T., Altay, S., Schubert, R. (2017) Src tyrosine kinases contribute to serotonin-mediated contraction by regulating calcium-dependent pathways in rat skeletal muscle arteries. Pflugers Arch 469, 767-777

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