Neprilysins regulate muscle contraction and heart function via cleavage of SERCA-inhibitory micropeptides.
Neprilysins regulate muscle contraction and heart function via cleavage of SERCA-inhibitory micropeptides.
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DOI：
10.1038/s41467-022-31974-1
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发表时间：
2022-07-29
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
肌肉收缩依赖于严格控制的心肌细胞内的钙瞬变。维持这些瞬间的一个主要参与者是肌浆/内质网钙ATPase，SERCA。SERCA的活性受微肽结合的调节，这些多肽的表达或功能受损会导致心肌病。到目前为止，还不知道微肽的动态平衡或周转是如何调节的。在这里，我们发现果蝇内肽酶Neprillysin 4在肌浆网的膜上水解SERCA抑制Sarcolamban多肽，从而确保SERCA的适当调节。切割是维持微肽的动态平衡和功能的必要条件和充分条件。对人脑纤溶素、肌磷脂和心肌细胞的分析表明，这种调节机制在进化上是保守的。通过确定neprilysin是心肌细胞SERCA活性和钙稳态的基本调节因子，这些数据有助于更全面地了解在健康和疾病中控制肌肉收缩和心脏功能的复杂机制。肌肉收缩依赖于严格控制的心肌细胞内的钙瞬变。在这里，作者表明，内肽酶Neprilysin 4代表了这些瞬变的基本调节因素，因此，对正常的心脏功能也是如此。
Muscle contraction depends on strictly controlled Ca2+ transients within myocytes. A major player maintaining these transients is the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase, SERCA. Activity of SERCA is regulated by binding of micropeptides and impaired expression or function of these peptides results in cardiomyopathy. To date, it is not known how homeostasis or turnover of the micropeptides is regulated. Herein, we find that the Drosophila endopeptidase Neprilysin 4 hydrolyzes SERCA-inhibitory Sarcolamban peptides in membranes of the sarcoplasmic reticulum, thereby ensuring proper regulation of SERCA. Cleavage is necessary and sufficient to maintain homeostasis and function of the micropeptides. Analyses on human Neprilysin, sarcolipin, and ventricular cardiomyocytes indicates that the regulatory mechanism is evolutionarily conserved. By identifying a neprilysin as essential regulator of SERCA activity and Ca2+ homeostasis in cardiomyocytes, these data contribute to a more comprehensive understanding of the complex mechanisms that control muscle contraction and heart function in health and disease. Muscle contraction depends on strictly controlled calcium transients within myocytes. Here, the authors show that the endopeptidase Neprilysin 4 represents an essential regulator of these transients and, consequently, of proper heart function.
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DOI：
10.1161/circgenetics.115.001254
发表时间：
2016-04
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Hartley PS;Motamedchaboki K;Bodmer R;Ocorr K
通讯作者：
Ocorr K
影响因子：
29
作者：
Gorski PA;Ceholski DK;Hajjar RJ
通讯作者：
Hajjar RJ
影响因子：
10.8
作者：
Fakuade FE;Steckmeister V;Seibertz F;Gronwald J;Kestel S;Menzel J;Pronto JRD;Taha K;Haghighi F;Kensah G;Pearman CM;Wiedmann F;Teske AJ;Schmidt C;Dibb KM;El-Essawi A;Danner BC;Baraki H;Schwappach B;Kutschka I;Mason FE;Voigt N
通讯作者：
Voigt N
影响因子：
5
作者：
Brodehl, Andreas;Dieding, Mareike;Milting, Hendrik
通讯作者：
Milting, Hendrik
影响因子：
4
作者：
Díaz, ME;Graham, HK;Eisner, DA
通讯作者：
Eisner, DA