The effect of myosin RLC phosphorylation in normal and cardiomyopathic mouse hearts.
The effect of myosin RLC phosphorylation in normal and cardiomyopathic mouse hearts.
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DOI：
10.1111/j.1582-4934.2011.01371.x
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发表时间：
2012-04
影响因子：
5.3
通讯作者：
Szczesna-Cordary D
中科院分区：
文献类型：
--
作者：
Muthu P;Kazmierczak K;Jones M;Szczesna-Cordary D
钙调蛋白激活的肌球蛋白轻链激酶（MLCK）对肌球蛋白调节轻链（RLC）的磷酸化是心脏变力功能所必需的。在这项研究中，我们研究了MLCK磷酸化的转基因（Tg）小鼠心肌制备表达D166 V（天冬氨酸到缬氨酸）-RLC突变，确定导致家族性肥厚型心肌病恶性结果的影响。我们以前的工作与Tg-D166 V小鼠表现出大量增加的Ca 2+敏感性的收缩，减少最大ATP酶和力和降低水平的内源性RLC磷酸化。基于证明心肌肌球蛋白磷酸化对心脏功能的有益和/或保护作用的研究，我们假设Tg-D166 V心肌的离体磷酸化可以挽救先前在单个肌球蛋白分子水平和Tg-D166 V乳头肌纤维中观察到的有害收缩表型。我们发现，MLCK诱导的Tg-D166 V心肌肌原纤维和肌纤维的磷酸化能够增加减少肌原纤维ATP酶和逆转异常增加的Ca 2+敏感性的力量，观察到的TG-野生型（WT）肌肉的水平。然而，与Tg-WT相反，Tg-D166 V乳头肌纤维中的最大张力在磷酸化后降低，Tg-WT显示磷酸化诱导的稳态力增加。除了力产生的数据，我们的研究结果支持的概念，RLC磷酸化作为一种救援机制，减轻有害的功能影响的疾病引起的突变。进一步的研究是必要的，以阐明这种意想不到的磷酸化诱导的最大张力降低在Tg-D166 V皮肤肌纤维的机制。
Phosphorylation of the myosin regulatory light chain (RLC) by Ca2+-calmodulin–activated myosin light chain kinase (MLCK) is known to be essential for the inotropic function of the heart. In this study, we have examined the effects of MLCK-phosphorylation of transgenic (Tg) mouse cardiac muscle preparations expressing the D166V (aspartic acid to valine)–RLC mutation, identified to cause familial hypertrophic cardiomyopathy with malignant outcomes. Our previous work with Tg-D166V mice demonstrated a large increase in the Ca2+ sensitivity of contraction, reduced maximal ATPase and force and a decreased level of endogenous RLC phosphorylation. Based on studies demonstrating the beneficial and/or protective effects of cardiac myosin phosphorylation for heart function, we hypothesized that an ex vivo phosphorylation of Tg-D166V cardiac muscle may rescue the detrimental contractile phenotypes observed earlier at the level of single myosin molecules and in Tg-D166V papillary muscle fibres. We showed that MLCK-induced phosphorylation of Tg-D166V cardiac myofibrils and muscle fibres was able to increase the reduced myofibrillar ATPase and reverse an abnormally increased Ca2+ sensitivity of force to the level observed for Tg-wild-type (WT) muscle. However, in contrast to Tg-WT, which displayed a phosphorylation-induced increase in steady-state force, the maximal tension in Tg-D166V papillary muscle fibres decreased upon phosphorylation. With the exception of force generation data, our results support the notion that RLC phosphorylation works as a rescue mechanism alleviating detrimental functional effects of a disease causing mutation. Further studies are necessary to elucidate the mechanism of this unexpected phosphorylation-induced decrease in maximal tension in Tg-D166V–skinned muscle fibres.
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影响因子：
4.7
作者：
Flavigny, J;Richard, P;Hainque, B
通讯作者：
Hainque, B
DOI：
10.1016/s0022-2828(03)00146-9
发表时间：
2003-07-01
影响因子：
5
作者：
Mörner, S;Richard, P;Waldenström, A
通讯作者：
Waldenström, A
DOI：
10.1073/pnas.77.6.3186
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
HILL, TL;EISENBERG, E;GREENE, L
通讯作者：
GREENE, L
影响因子：
5
作者：
Muthu, Priya;Mettikolla, Prasad;Borejdo, J.
通讯作者：
Borejdo, J.
影响因子：
10.8
作者：
Abraham, Theodore P.;Jones, Michelle;Szczesna-Cordary, Danuta
通讯作者：
Szczesna-Cordary, Danuta