Src family protein tyrosine kinases modulate L-type calcium current in human atrial myocytes |
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Authors: | Bogdelis Andrius Treinys Rimantas Stankevičius Edgaras Jurevičius Jonas Skeberdis V Arvydas |
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Affiliation: | aLithuanian University of Health Sciences, Institute of Cardiology, 50009 Kaunas, Lithuania;bLithuanian University of Health Sciences, Department of Physiology, 44307 Kaunas, Lithuania |
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Abstract: | In the heart, L-type voltage dependent calcium channels (L-VDCC) provide Ca2+ for the activation of contractile apparatus. The best described pathway for L-type Ca2+ current (ICa,L) modulation is the phosphorylation of calcium channels by cAMP-dependent protein kinase A (PKA), the activity of which is predominantly regulated in opposite manner by β-adrenergic (β-ARs) and muscarinic receptors. The role of other kinases is controversial and often depends on tissues and species used in the studies. In different studies the inhibitors of tyrosine kinases have been shown either to stimulate or inhibit, or even have a biphasic effect on ICa,L. Moreover, there is no clear picture about the route of activation and the site of action of cardiac Src family nonreceptor tyrosine kinases (Src-nPTKs). In the present study we used PP1, a selective inhibitor of Src-nPTKs, alone and together with different activators of ICa,L, and demonstrated that in human atrial myocytes (HAMs): (i) Src-nPTKs are activated concomitantly with activation of cAMP-signaling cascade; (ii) Src-nPTKs attenuate PKA-dependent stimulation of ICa,L by inhibiting PKA activity; (iii) Gαs are not involved in the direct activation of Src-nPTKs. In this way, Src-nPTKs may provide a protecting mechanism against myocardial overload under conditions of increased sympathetic activity. |
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Keywords: | Abbreviations: L-VDCC, L-type voltage dependent calcium channels ICa,L, L-type calcium current PKA, protein kinase A β-ARs, β-adrenergic receptors Src-nPTKs, Src family nonreceptor protein tyrosine kinases HAMs, human atrial myocytes ISO, isoprenaline AC, adenylyl cyclase |
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