Effect of protein kinase A on calcium sensitivity of force and its sarcomere length dependence in human cardiomyocytes

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Objective: We investigated whether the Frank-Starling mechanism is absent or preserved in end-stage failing human myocardium and if phosphorylation of contractile proteins modulates its magnitude through the sarcomere length-dependence of calcium sensitivity of isometric force development. Methods: The effect of phosphorylation of troponin I and C-protein by the catalytic subunit of protein kinase A (3 μg/ml; 40 min at 20°C) was studied in single Triton-skinned human cardiomyocytes isolated from donor and end-stage failing left ventricular myocardium at sarcomere lengths measured at rest of 1.8, 2.0 and 2.2 μm. Isometric force development was studied at various free-calcium concentrations before and after protein kinase A incubation at 15°C (pH 7.1). Results: Maximal isometric tension at 2.2 μm amounted to 39.6±10.4 and 33.7±3.5 kN/m 2 in donor and end-stage failing cardiomyocytes, respectively. The midpoints of the calcium sensitivity curves (pCa 50 ) of donor and end-stage failing hearts differed markedly at all sarcomere lengths (mean ΔpCa 50 =0.22). A reduction in sarcomere length from 2.2 to 1.8 μm caused reductions in maximum isometric force to 64% and 65% and in pCa 50 by 0.10 and 0.08 pCa units in donor and failing cardiomyocytes, respectively. In donor tissue, the effect of protein kinase A treatment was rather small, while in end-stage failing myocardium it was much larger (ΔpCa 50 =0.24) irrespective of sarcomere length. Conclusions: The data obtained indicate that the Frank-Starling mechanism is preserved in end-stage failing myocardium and suggest that sarcomere length dependence of calcium sensitivity and the effects of phosphorylation of troponin I and C-protein are independent. Copyright (C) 2000 Elsevier Science B.V.




Van Der Velden, J., De Jong, J. W., Owen, V. J., Burton, P. B. J., & Stienen, G. J. M. (2000). Effect of protein kinase A on calcium sensitivity of force and its sarcomere length dependence in human cardiomyocytes. Cardiovascular Research, 46(3), 487–495. https://doi.org/10.1016/S0008-6363(00)00050-X

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