A novel phosphorylation site, Serine 199, in the C-terminus of cardiac troponin I regulates calcium sensitivity and susceptibility to calpain-induced proteolysis

Journal of Molecular and Cellular Cardiology
Paul J M WijnkerJolanda van der Velden

Abstract

Phosphorylation of cardiac troponin I (cTnI) by protein kinase C (PKC) is implicated in cardiac dysfunction. Recently, Serine 199 (Ser199) was identified as a target for PKC phosphorylation and increased Ser199 phosphorylation occurs in end-stage failing compared with non-failing human myocardium. The functional consequences of cTnI-Ser199 phosphorylation in the heart are unknown. Therefore, we investigated the impact of phosphorylation of cTnI-Ser199 on myofilament function in human cardiac tissue and the susceptibility of cTnI to proteolysis. cTnI-Ser199 was replaced by aspartic acid (199D) or alanine (199A) to mimic phosphorylation and dephosphorylation, respectively, with recombinant wild-type (Wt) cTn as a negative control. Force development was measured at various [Ca(2+)] and at sarcomere lengths of 1.8 and 2.2 μm in demembranated cardiomyocytes in which endogenous cTn complex was exchanged with the recombinant human cTn complexes. In idiopathic dilated cardiomyopathy samples, myofilament Ca(2+)-sensitivity (pCa50) at 2.2 μm was significantly higher in 199D (pCa50 = 5.79 ± 0.01) compared to 199A (pCa50 = 5.65 ± 0.01) and Wt (pCa50 = 5.66 ± 0.02) at ~63% cTn exchange. Myofilament Ca(2+)-sensitivity was significantly highe...Continue Reading

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Citations

Feb 28, 2016·Archives of Biochemistry and Biophysics·Jennifer E GildaAldrin V Gomes
Apr 1, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Xue WangJun Qu
May 19, 2018·American Journal of Physiology. Heart and Circulatory Physiology·Victoria N ParikhEuan A Ashley
Oct 7, 2017·Expert Review of Proteomics·Daniel SoetkampJennifer Van Eyk
Nov 1, 2018·Physiological Reviews·Jolanda van der Velden, Ger J M Stienen
Mar 15, 2021·Biochemical and Biophysical Research Communications·William LehmanMichael J Rynkiewicz

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