期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 79, 期 -, 页码 264-274出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2014.11.022
关键词
Myocyte; Myofilament; Troponin; Protein kinase C; Phosphorylation
资金
- National Institutes of Health Grant [R01-HL-067254, P60-DK20572]
- NIGMS [T32 GM007315]
- American Heart Association pre-doctoral award [12PRE8830022]
- NIH [R25 HL108842]
Protein kinase C (PKC) targets cardiac troponin I (cTnI) S43/45 for phosphorylation in addition to other residues. During heart failure, cTnI 543/45 phosphorylation is elevated, and yet there is ongoing debate about its functional role due, in part, to the emergence of complex phenotypes in animal models. The individual functional influences of phospholylated 543 and 545 also are not yet known. The present study utilizes viral gene transfer of cTnI with phosphomimetic 543D and/or S45D substitutions to evaluate their individual and combined influences on function in intact adult cardiac myocytes. Partial replacement (<= 40%) with either cTnIS43D or cTnIS45D reduced the amplitude of contraction, and cTnIS45D slowed contraction and relaxation rates, while there were no significant changes in function with cTnIS43/45D. More extensive replacement (>= 70%) with cTnIS43D, cTnIS45D, and cTnIS43/45D each reduced the amplitude of contraction. Additional experiments also showed cTnIS45D reduced myofilament Ca2+ sensitivity of tension. At the same time, shortening rates returned toward control values with cTnIS45D and the later stages of relaxation also became accelerated in myocytes expressing cTnIS43D and/or S45D. Further studies demonstrated this behavior coincided with adaptive changes in myofilament protein phosphorylation. Taken together, the results observed in myocytes expressing cTnIS43D and/or S45D suggest these 2 residues reduce function via independent mechanism(s). The changes in function associated with the onset of adaptive myofilament signaling suggest the sarcomere is capable of fine tuning PKC-mediated cTnIS43/45 phosphorylation and contractile performance. This modulatory behavior also provides insight into divergent phenotypes reported in animal models with cTnI 543/45 phosphomimetic substitutions. (C) 2014 Elsevier Ltd. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据