Junctophilin and excitation-contraction coupling in skeletal muscles

doi:10.3969/j.issn.2095-4344.1094

Abstract

Abstract:

BACKGROUND: Skeletal muscle is the power organ in human, and its excitation-contraction coupling structure and efficacy play important roles in movement and sport abilities of players. Junctophilin can sustain the ultrastructure of thribble and constitutes the coupling membrane complex, thus providing a structural basis for signal transduction between cell membrane and sarcoplasmic reticulum.
OBJECTIVE: To summarize the fascia, thribble and excitation-contraction coupling of skeletal muscle, as well as type and function of junctophilin, and its association with diseases.
METHODS: CBM, CNKI, PubMed and Elsevier databases were searched for the articles concerning excitation-contraction coupling of skeletal muscle and junctophilin published from September 1987 to April 2018. The keywords were “skeletal muscle, fascia, the triad junction, excitation-contraction coupling, junctophilins” in English and Chinese, respectively. Finally 39 eligible articles were enrolled after excluding irrelevant articles.
RESULTS AND CONCLUSION: Thribble is the foundational structure for excitation-contraction coupling, whose transverse tubule is the extension of fascia. There are some small-molecule proteins on the thribble membrane, which are critical for sustaining the structure and function of thribble. Meanwhile, junctophilin is an important bridge between longitudinal and transverse tubules of thribble. Junctophilin 1 is an important factor on the membrane of thribble and a part of the coupling membrane complex, which connects the cytoplasmic membrane with sarcoplasmic reticulum, and thereby sustains the normal morphology and count of the thribble. Thereafter, calcium signal transduction remains normal, which ensures the process of excitation-contraction coupling. Junctophilin damage is related to various diseases, so it is a promising target for disease treatment and provides idea for molecular intervention.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Muscle, Skeletal, Fascia, Excitation Contraction Coupling, Tissue Engineering

CLC Number:

R446

Li Wenhui. Junctophilin and excitation-contraction coupling in skeletal muscles[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(11): 1799-1804.

Figures/Tables 1

2.1 骨骼肌兴奋收缩偶联 2.1.1 筋膜系统人体是由不同密度的结缔组织交织成的网状结构(筋膜)构成的，各种器官“镶嵌”其中，由筋膜悬吊、包裹、分离和联系[5]，各种血管和神经也走行于筋膜中，联系着全身。因此，人体为一个有机整体，“牵一发而能动全身”。骨骼肌是人体动力器官，是生命的基本机器。根据筋膜理论，骨骼肌的运动与内脏器官的位置、形态和功能相关。因肌肉的运动不良，会导致器官功能失调，进而引起组织成分的改变，从而导致疾病的发生。骨骼肌的筋膜包括肌外膜、肌束膜和肌内膜。肌外膜包绕整块骨骼肌，并与其他器官相联系。肌外膜向肌肉内延伸，将肌肉分离成束，称为肌束膜。肌束膜继续往肌肉深部延伸，包裹每一根肌纤维，称其为肌内膜，即胞浆膜[6]。但是，筋膜系统并没就此停止，而是继续向肌纤维深处延伸，只是不再像肌外膜、肌束膜、肌内膜那样纵向包裹，而是横向切入，于是构成了骨骼肌的横管系统[7]。 2.1.2 三联管骨骼肌的兴奋收缩偶联为肌细胞的膜电位变化与肌丝滑行之间的偶联，其结构基础为三联管[3]。骨骼肌由很多成束的肌纤维(肌细胞)构成，每条肌纤维含有成百上千条并行的肌原纤维。偶联膜复合体联系胞浆膜(plasma membrane，PM)和肌浆网，介导胞浆膜的电兴奋和肌肉收缩之间的偶联信号，它对胞外Ca2+流入与SR的Ca2+储存调控的Ca2+释放机制起着重要作用[8]。心肌的偶联膜复合体叫做二联管，而骨骼肌的偶联膜复合体被称作三联管。骨骼肌纤维的偶联膜复合体由两套肌管系统组成：横管系统和纵管系统。横管与其两旁膨起的纵管(终池)联合构成三联管[3]。横管为肌膜垂直于肌原纤维走向，凹入肌浆内而形成的管状结构，又称T管，该结构为肌膜信号传入肌细胞深部提供了结构基础。横管在肌纤维的Z线水平，即明带和暗带交界处。肌纤维中横管数目由于肌纤维类型的不同而不同，也由于物种不同而有差异，但同一种肌细胞的横管数目基本一致。横管包括结合部与游离部，结合部为直扁管，为去极化电信号由横管传到SR的位置，又称偶联部。游离部主要为小曲管，截面像圆形。结合部与游离部的比例根据肌纤维类型的不同而有所不同[9]。纵管系统包绕于肌原纤维周围，似套筒状，和肌原纤维相平行，又名L管。纵管其实是肌细胞的SR，由于SR里面有许多Ca2+而被称作肌细胞内的Ca2+库。纵管在接近横管的地方膨大呈扁囊状，称作终池。横管与其侧仅有的一个终池偶联构成二联管，心肌内常见该结构。横管与其两侧的2个终池联合组成的三联管为骨骼肌的特有结构，乃兴奋收缩偶联的重要结构基础[10]。 2.1.3 兴奋收缩偶联肌丝滑行学说是研究者们目前公认的肌肉收缩机制，肌球蛋白与肌动蛋白结合的位点被肌钙蛋白牵拉的原肌球蛋白覆盖，当胞浆内Ca2+的浓度升高时，肌钙蛋白与Ca2+结合而变构，肌钙蛋白不再牵拉原肌球蛋白，原肌球蛋白就滑入肌动蛋白沟中，导致位点暴露，肌球蛋白横桥球状头部和肌动蛋白位点迅速结合，借助ATP提供能量，拉着肌动蛋白末端向中央滑动，产生了肌肉收缩。由此可见，Ca2+是调控肌肉收缩的关键因子，骨骼肌的兴奋收缩偶联就是通过调控Ca2+的浓度变化，将细胞膜的膜电位变化与肌丝滑行联系起来。骨骼肌兴奋收缩偶联包含3个基本过程：①动作单位沿横管传入肌肉深部，三联管膜上的Ca2+通道被激活；②Ca2+迅速由胞外涌入胞浆，同时SR中Ca2+也释放入胞浆，胞浆中Ca2+浓度急剧上升，肌钙蛋白和Ca2+结合，肌肉开始缩短；③胞浆中Ca2+浓度升高至一定程度，激活SR膜的Ca2+泵，Ca2+被回纳入SR，胞浆中Ca2+浓度下降，肌肉开始舒张[11]。由此可见，兴奋收缩偶联是通过Ca2+浓度来传递信号，并促成肌纤维的收缩和舒张的。骨骼肌内有两种调控胞浆内Ca2+浓度的机制，一种是电压门控的钙离子释放(voltage-induced Ca2+ release，VICR)，是去极化信号传至胞浆膜，因膜电位变化引起的钙离子内流；另一种是钙致钙释放(Ca2+-induced Ca2+ release，CICR) 机制，是指当肌钙蛋白与Ca2+结合导致胞浆内Ca2+浓度急剧降低时，导致肌浆网将储存的钙离子释放入胞浆[2]，钙致钙释放机制在肌肉疲劳时发挥重要作用[12]。三联管膜上有多种蛋白，对维持三联管的正常结构和发挥兴奋收缩偶联功能起着重要作用。双氢吡啶受体蛋白栖身横管膜的偶联部，通过电压门控的钙离子释放机制调控兴奋收缩偶联，其L型Ca2+通道变构会使胞外的Ca2+涌入胞内；RyR1的足状结构朝横管膜的偶联区伸展，与双氢吡啶受体蛋白以2∶1比率形成偶联，而RyR1复合区较大，嵌入肌浆网膜，当RyR1足状结构探知双氢吡啶受体蛋白变构与三联管区钙离子浓度改变时，RyR1构象快速出现变化，使SR内的Ca2+也被释放入胞浆，所以它是通过钙致钙释放调控兴奋收缩偶联[3]。双氢吡啶受体蛋白与RyR1的偶联结构使胞外的钙离子流入与肌浆网内的钙离子释放相呼应，保证了兴奋收缩偶联功能的发挥。MG29蛋白位于横管膜，在三联管和SR的早期发育中发挥关键作用，敲除MG29的骨骼肌的SR结构构型紊乱，呈现空泡、破碎，以及兴奋收缩脱偶联。MG29蛋白还能直接调控RYR1，使SR释放Ca2+到胞浆，也能察知SR内的Ca2+含量，进而调动细胞外的Ca2+进入胞内以补充SR耗空的的Ca2+库[13]。此外，还有Calumin、STIM1、亲联蛋白、Orai、TRIC等对三联管结构的维持和兴奋收缩偶联功能的发挥起着重要作用[3，14-16]。 2.2 亲联蛋白(junctophilin，JPH) Takeshima等[17]研究者在2000年借助单细胞克隆手段在三联管部发现了两种蛋白成分，这些蛋白质对三联管复合结构的形成和其正常形态的保持发挥重要作用，其中之一就是junctophilin。 2.2.1 亲联蛋白分型亲联蛋白的大部置身细胞浆中，它的氨基酸残基可以选择性与细胞膜相结合，另有1个羧基的尾端与肌浆网的终池膜相连，所以亲联蛋白有联系横管系统和肌浆网的功能[4]。研究者在人和小鼠体内发现了亲联蛋白的4种亚型：见表1。"

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