Effect and mechanism of TRPC1 channel regulating function of vascular smooth muscle cells

doi:10.3969/j.issn.2095-4344.0557

Abstract

Abstract:

BACKGROUND: The function of vascular smooth muscle cells is closely related to the occurrence of vascular diseases. TRPC1 channel can regulate the function of vascular smooth muscle cells.
OBJECTIVE: To summarize the effect of TRPC1 channel on the fine function of vascular smooth muscle, and to discuss the underlying mechanisms.
METHODS: A computer-based retrieval of Beijing University of Aeronautics and Astronautics Library, CNKI, Baidu Academic and PubMed Central Medline was conducted for the literature addressing vascular smooth muscle cells and TRPC1 channel from 1969 to 2017. The keywords were “vascular smooth muscle cells, TRPC1 channel, vascular smooth muscle cells function” in English and Chinese, respectively. Finally, 1 Chinese article and 44 English articles were enrolled.
RESULTS AND CONCLUSION: TRPC1 channel is one of the non-selective cation channel superfamily TRP and widely expressed on vascular smooth muscle, which regulates vascular smooth muscle cell function. Since its discovery, the TRPC1 channel has been identified as one of the store-operated Ca2+ channels in cells due to its contribution to the store-operated Ca2+ entry. We have got a lot of research results on the TRPC1 channel effect on vascular smooth muscle cells by gene knockout, RNAi, mRNA blocking and specific blocking antibodies and other research methods. In this paper, the results of the current study on the effect of TRPC1 channel on vascular smooth muscle cells are summarized, and the possible mechanism is discussed.

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: Tissue Engineering, Calcium Channels, Patch-Clamp Techniques

CLC Number:

R318

Gao Chao1, Jia Xiao-ling1, Rong Li-jun2 . Effect and mechanism of TRPC1 channel regulating function of vascular smooth muscle cells [J]. Chinese Journal of Tissue Engineering Research, 2018, 22(32): 5228-5233.

Figures/Tables 1

2.1 TRPC1通道简介离子通道是广泛表达在各种细胞上的特殊的亲水性蛋白质孔道，是多种细胞生命活动的分子基础。近年来，随多种细胞分子生物学研究手段的发展，人们对多种离子通道的结构特性和生物学功能有了更加深入的了解，发现了离子通道的异常会对各种细胞的功能产生显著的影响，严重的会致使细胞功能异常，进而导致多种疾病的发生。因此，研究细胞上的离子通道，对治疗各种由离子通道结构和功能异常引起的疾病有重要的指导意义。 TRP通道是一个非选择性阳离子通道的超家族，作为细胞的传感器和效应器，调控多种细胞功能[1]。第一个TRP通道于1969年由Cosens和Manning在一种果蝇突变体的光感受器细胞上发现。在持续的光刺激下，野生型的果蝇光感受细胞会产生持续的细胞内钙浓度的升高，而突变体的果蝇光感受器细胞只能产生短暂的细胞内钙浓度升高，因此这种突变的基因被命名为TRP通道[2]。随后，在哺乳动物中，大量的TRP通道被克隆出来[3]。到目前为止，哺乳动物TRP通道超家族共有28名成员，基于结构的相似性，它们被划分为6个亚家族：TRPC(Canonical)，TRPM(Melastatin)，TRPML (Mucolipins)，TRPV(Vanilloid)，TRPP(Policystin)和TRPA(Ankyrin-rich protein)[4]，其中TRPC通道因其在结构上与最早在果蝇中发现的TRP通道类似而得名[5]。哺乳动物的TRPC通道目前共有7种，根据结构的同源性，功能的相似性和已知的相互作用，TRPC家族又可以划分为4类：TRPC1，TRPC2，TRPC3/6/7和TRPC4/5 (TRPC1有时包括在TRPC4/5中)[5-7]。TRPC1是第一个被发现的哺乳动物TRP通道蛋白[8]，目前已有大量文献报道揭示其结构和特性，以及其在各种细胞中的功能。 2.1.1 TRPC1通道基因简介 1995年，人类TRPC1通道的DNA和对应的氨基酸序列以及表达模式被公布出来。编码人类TRPC1通道的基因位于3号染色体上[8]。目前发现TRPC1通道的mRNA共有5种剪接变体，分别是：TRPC1α，TRPC1β，TRPC1γ，TRPC1δ和TRPC1ε，但似乎只有3个(TRPC1α，TRPC1β和TRPC1ε)能被翻译成为有功能的通道蛋白。其中TRPC1β在第3个锚蛋白重复序列中缺少34个氨基酸残基，TRPCε则是在第一个跨膜螺旋结构域的下游有7个氨基酸残基的缺失[9-10](锚蛋白重复序列和跨膜螺旋结构域将在下一部分进行介绍)。由公布的DNA序列推测的TRPC1α和TRPC1β通道蛋白的相对分子质量应该分别是91 200和87 600，然而，在正常组织中，TRPC1通道蛋白的实际相对分子质量要大于这个大小。这个差异最初被认为是由通道蛋白的第5个跨膜结构域和孔通道区域的糖基化所导致的[11](跨膜螺旋结构域和孔通道区域将在下一部分进行介绍)。然而，有研究发现在公布的起始密码子AUG的上游，存在另一个起始密码子CUG，从该起始密码子处开始翻译，会导致得到的TRPC1通道蛋白的氨基末端延伸出78个氨基酸残基，这段延伸出的序列含有一簇带正电的氨基酸残基[10]，此现象的生理功能尚不明确。有人推测，这是一种TRPC1通道功能的自我调控机制，即当TRPC1通道蛋白发生构象转变时，这个带正电荷的区域可能会阻断其带负电荷的孔通道区，使TRPC1通道关闭[12]。另外，TRPC1ε还存在一个在第5外显子上带有34个核苷酸残基缺失的有功能的剪接变体[10]。 2.1.2 TRPC1通道蛋白简介 TRPC1通道蛋白由6个跨膜结构片段(S1-S6)以及在胞质内的N端和C端组成。在第5和第6个跨膜结构片段之间有个胞外环，这个区域主要是由带负电荷的谷氨酸和天冬氨酸构成的α螺旋结构，是TRPC1通道的离子通透区。TRPC1通道蛋白的N 端有1个螺旋区(CC)和4个锚蛋白重复区(AAAA)，人们推测它们可能参与了TRPC1通道蛋白在细胞上的锚定，其中的锚蛋白重复区还可能参与调控通道蛋白的同源多聚化。与所有其他所有的TRPC通道蛋白的结构类似，TRPC1通道蛋白的C端有一个功能未知的TRP盒结构(氨基酸残基序列为EWKFAR)以及两个钙调蛋白(Calmodulin，CaM)结合位点，后者参与调控钙离子诱导的TRPC1通道电流的失活。此外，TRPC1通道蛋白C端的2个带负电荷的天冬氨酸残基(Asp639和Asp640)能与钙感受器-基质相互作用分子1(Stromal interacting molecule 1，STIM1)上的2个带正电荷的赖氨酸残基(Lys684和Lys685)相互作用，调控TRPC1通道的开放与关闭[13]。 2.2 TRPC1通道对血管平滑肌细胞功能的影响 2.2.1 血管平滑肌细胞简介血管平滑肌细胞位于血管壁的中层，是血管壁的重要细胞组分之一。在胚胎发生期，血管平滑肌细胞由三胚层中的中胚层发育而来，发育成熟的血管平滑肌细胞所具有的特征表型为收缩表型(contractile phenotype)，这种表型的血管平滑肌细胞主要执行收缩功能，其收缩与舒张能维持血管结构的完整性，调节血压和血流分布[14]。在正常情况下，成人血管系统内的平滑肌细胞的特征是极低的增殖速率，非常低的合成活性和表达一系列独特的离子通道、收缩蛋白和信号分子，这对维持其功能尤为重要[14-16]。不同解剖学位置的血管平滑肌细胞表达不同类型的离子通道，这些特定的通道表达模式在明确平滑肌细胞的表型时非常重要[17-18]。不同于终末分化的心肌细胞和骨骼肌细胞，血管平滑肌细胞仍保留着一定的表型可塑性，表现为它们可以对体液，环境和病理生理指标的刺激做出应答，在某些因素，如生长因子(growth factor)，炎症反应(inflammatory response)和力学因素(mechanical factors)等的刺激下，收缩表型的血管平滑肌细胞可能会暂时去分化，重新转变为未分化的更接近胚胎期的表型，即合成表型(synthetic phenotype)[14]。动脉血管壁结构和受力示意图见图1。此种表型的血管平滑肌细胞表现出显著的增殖和迁移的特性，并且在其增殖和迁移的同时会合成和分泌细胞外基质和多种细胞因子等[15，17]，这也是导致许多血管疾病，如高血压(hypertension)、动脉粥样硬化(atherosclerosis)、血管成形术后再狭窄(restenosis)等发生的重要原因[14]。因此，研究血管平滑肌细胞的功能改变及其机制，对许多血管疾病的治疗有着重要的意义。"

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