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lüll The multifunctional Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKIIdelta) phosphorylates cardiac titin s spring elements Hidalgo CG; Chung CS; Saripalli C; Methawasin M; Hutchinson KR; Tsaprailis G; Labeit S; Mattiazzi A; Granzier HLJ Mol Cell Cardiol 2013[Jan]; 54 (ä): 90-7Titin-based passive stiffness is post-translationally regulated by several kinases that phosphorylate specific spring elements located within titin's elastic I-band region. Whether titin is phosphorylated by calcium/calmodulin dependent protein kinase II (CaMKII), an important regulator of cardiac function and disease, has not been addressed. The aim of this work was to determine whether CaMKIIdelta, the predominant CaMKII isoform in the heart, phosphorylates titin, and to use phosphorylation assays and mass spectrometry to study which of titin's spring elements might be targeted by CaMKIIdelta. It was found that CaMKIIdelta phosphorylates titin in mouse LV skinned fibers, that the CaMKIIdelta sites can be dephosphorylated by protein phosphatase 1 (PP1), and that under baseline conditions, in both intact isolated hearts and skinned myocardium, about half of the CaMKIIdelta sites are phosphorylated. Mass spectrometry revealed that both the N2B and PEVK segments are targeted by CaMKIIdelta at several conserved serine residues. Whether phosphorylation of titin by CaMKIIdelta occurs in vivo, was tested in several conditions using back phosphorylation assays and phospho-specific antibodies to CaMKIIdelta sites. Reperfusion following global ischemia increased the phosphorylation level of CaMKIIdelta sites on titin and this effect was abolished by the CaMKII inhibitor KN-93. No changes in the phosphorylation level of the PEVK element were found suggesting that the increased phosphorylation level of titin in IR (ischemia reperfusion) might be due to phosphorylation of the N2B element. The findings of these studies show for the first time that titin can be phosphoryalated by CaMKIIdelta, both in vitro and in vivo, and that titin's molecular spring region that determines diastolic stiffness is a target of CaMKIIdelta.|*Protein Processing, Post-Translational[MESH]|Amino Acid Motifs[MESH]|Amino Acid Sequence[MESH]|Animals[MESH]|Calcium-Calmodulin-Dependent Protein Kinase Type 2/*chemistry/metabolism[MESH]|Conserved Sequence[MESH]|Heart Ventricles/pathology[MESH]|Humans[MESH]|In Vitro Techniques[MESH]|Male[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Molecular Sequence Data[MESH]|Myocardial Reperfusion Injury/enzymology[MESH]|Myocytes, Cardiac/enzymology[MESH]|Phosphorylation[MESH]|Protein Kinases/*chemistry/metabolism[MESH]|Protein Structure, Tertiary[MESH] |