瞬时受体电位M4通道与心脏电活动及心律失常的研究进展

瞬时受体电位M4(TRPM4)是由Ca~(2+)激活的非选择性阳离子通道,最新研究利用低温电子显微镜诠释了TRPM4通道蛋白的结构。TRPM4广泛存在于心血管系统中,且参与心肌细胞动作电位的各个阶段。几项研究已经确定TRPM4突变引起的遗传性心脏病患者临床表现包括传导阻滞和Brugada综合征。另外TRPM4也与心脏肥大引起的心律失常密切相关。     

瞬时受体电位1与心血管疾病关系研究进展

<正>近年来,以高血压、冠心病等为主要疾病谱的心血管疾病,发病率、病死率呈逐年上升趋势。研究发现,经典瞬时受体电位(TRPC)在心血管疾病的发生、发展中扮演了重要的角色。TRPC通道是钙库操控性通道(SOCs)的成员之一,位于胞膜,并介导Ca~(2+)跨膜转运,影响细胞的增殖、迁移等基本生物学行为。而TRPC1是至今研究最多、最热门、也最受重视的一个TRPC亚型。近年对其研究发现,它与心血管疾病的发生、发展密切相关。现对TRPC1在心血管疾病中的研究现状及进展,作一综述。     

瞬时受体电位C通道与糖尿病的相关性研究进展

瞬时受体电位通道是细胞膜上一类重要的非选择性阳离子通道.1969年,Cosens和Manning[1]发现,突变体果蝇的视觉系统在持续性光刺激后可产生一种瞬时而非持续的峰电位,瞬时受体电位通道因此得名.在哺乳动物中,研究人员已发现28种瞬时受体电位通道亚型,依据氨基酸序列的同源性分属于6个亚家族[2],其中瞬时受体电位C通道是瞬时受体电位通道家族中最早发现的成员,与果蝇属的瞬时受体电位通道同源性最高.     

瞬时受体电位通道C亚族在心血管疾病中的研究进展

瞬时受体电位通道C亚族（canonical transient receptorpotential,TRPC）是位于细胞膜上的一种非选择性阳离子通道蛋白,分为7种亚型（TRPC1-7）,其中TRPC2在人类是假基因。近年来研究发现,TRPC通道的激活与高血压、肺动脉高压、心室重构、扩张性心肌病及动脉粥样硬化等心血管疾病发生、发展关系密切。血管紧张素Ⅱ、三磷酸腺苷、内皮素、去甲肾上腺素、加压素、乙酰胆碱、多种生长因子、钙池的衰竭和膜牵张等诸多因素都能够激活TRPC通道。根据激活机制的不同,TRPC通道可分为受体操纵性通道（receptor-operated channels,ROC）和储存操纵性通道（store-operated channels,SOC）。两个途径的激活均可改变阳离子(如Ca²⁺和Na⁺)内流,从而在调节心血管系统的功能方面发挥重要作用。本综述集中阐述TRPC通道C亚族在心血管疾病中的最新研究进展。     

瞬时受体电位M4通道相关的心脏疾病

瞬时受体电位通道(TRP)4是Ca2+激活的非特异性阳离子通道,参与心脏电活动的产生和传导。当其基因突变导致功能缺失时可通过减少钠通道Nav1.5或抑制电压依赖性钠通道的开放,降低心脏传导速度,从而引发心脏传导阻滞;在心肌肥厚时引起肥大心肌细胞的后除极化,导致致心律失常电重构及心律失常。TRPM4发挥作用的潜在分子机制,还需进一步研究。     

瞬时受体电位香草酸亚型4在心血管疾病中的研究进展

瞬时受体电位香草酸亚型4(TRPV4)是一种对渗透敏感、通过容量调节的非选择性阳离子通道。研究发现其在多种系统中均发挥重要作用。近年来越来越多的研究开始探索TRPV4在心血管疾病中的作用,包括动脉粥样硬化、高血压、心肌梗死、心律失常等。然而在不同的研究中,TRPV4的作用存在一定的争议。基于此,现综述近年来关于TRPV4在心血管疾病中的研究进展,以期更深入地了解该通道在心血管系统中的作用,为后续研究提供理论基础。     

瞬时受体电位通道与心律失常的关系

瞬时受体电位通道(TRP)超家族组成超过50种阳离子通道,分布在几乎所有心血管组织中,可以整合多种物理和化学的刺激诱导Ca2+进入胞内。TRP通道家族对心脏节律的维持起着关键作用:TRPC可能通过钙池操纵Ca2+通道参与起搏调控;肥厚心肌中TRPM4表达上调,通过瞬时性内向电流(Iti)参与延迟后除极的发生;TR-PC1和TRPC6参与牵张诱发性心律失常的发生;在缺血缺氧的病理条件下,ATP/UTP的释放激活TRPC3/7引发心电异常。将来有望通过干预TRP活性来开发新一代的抗心律失常药物。     

瞬时受体电位通道3与心房颤动

瞬时受体电位通道3(TRPC3)是一种非电压门控非选择性阳离子通道,在心血管系统中广泛分布,特别是在心房成纤维细胞中作为调控Ca2+稳态的关键通道.心房颤动是临床上最常见的快速性心律失常之一,心房结构重构和电重构是其发生的症结所在,纤维化作为结构重构的病理基础,是胶原纤维蓄积所导致.研究证实,TRPC3基因突变或过表达...     

瞬时受体电位阳离子通道蛋白6与糖尿病肾病

糖尿病肾病(DN)是糖尿病(DM)主要而严重的慢性并发症之一,30％ ～ 40％的终末期肾病患者来自于DN.最近的研究结果发现,瞬时受体阳离子通道蛋白6(TRPC6)与DN密切相关.TRPC6在肾小球表达异常,使系膜细胞及足细胞的钙内流异常而引起足细胞数量减少、肾小球高滤过、胞外基质(ECM)增多、肾小球基底膜(GBM)增厚,参与了DN的发生发展.我们现对TRPC6表达异常与DN的关系及治疗前景作一综述.     

瞬时受体电位C通道与心肌肥厚的研究进展

瞬时受体电位C(transient receptor potential canonical,TRPC)通道作为一类重要的非选择性阳离子通道,在心脏具有广泛的分布和表达。TRPC通道通过改变细胞膜电位和介导钙离子(Ca2+)内流对心脏的生理和病理反应产生重要影响。细胞内Ca2+不仅在心肌细胞的兴奋-收缩偶联中发挥重要作用,而且与各类心脏疾病发生密切相关。最近研究发现,TRPC通道可以通过调节细胞内Ca2+变化,与钙调磷酸酶(calcineurin,CaN)和活化的T细胞核因子(nuclear factor of activated T cells,NFAT)等效应因子参与心肌肥厚的发生发展过程,同时可诱导其他心脏疾病（如心肌纤维化、心率失常、心力衰竭）的发生。本文根据相关研究,围绕TRPC通道在心肌肥厚及相关心脏疾病的发生发展中的作用进行总结回顾。     

TRP channels: molecular diversity and physiological function

Calcium ions (Ca(2+)) are particularly important in cellular homeostasis and activity. To elicit physiologically relevant timing and spatial patterns of Ca(2+) signaling, ion channels in the surface of each cell precisely control Ca(2+) influx across the plasma membrane. A group of surface membrane ion channels called receptor-activated cation/Ca(2+) channels (RACCs) are activated by diverse cellular stimuli from the surrounding extracellular environment via receptors and other pathways such as heat, osmotic pressure, and mechanical and oxidative stress. An important clue to understanding the molecular mechanisms underlying the functional diversity of RACCs was first attained by molecular identification of the transient receptor potential (trp) protein (TRP), which mediates light-induced depolarization in Drosophila photoreceptor cells, and its homologues from various biological species. Recent studies have revealed that respective TRP channels are indeed activated by characteristic cellular stimuli. Furthermore, the involvement of TRP channels has been demonstrated in the signaling pathways essential for tissue-specific functions as well as ubiquitous biological responses, such as cell proliferation, differentiation, and death. These findings encourage the usage of TRP channels and their signalplexes as powerful tools for developing novel pharmaceutical targets.     

Attenuation of store-operated Ca2+ current impairs salivary gland fluid secretion in TRPC1(-/-) mice

Agonist-induced Ca(2+) entry via store-operated Ca(2+) (SOC) channels is suggested to regulate a wide variety of cellular functions, including salivary gland fluid secretion. However, the molecular components of these channels and their physiological function(s) are largely unknown. Here we report that attenuation of SOC current underlies salivary gland dysfunction in mice lacking transient receptor potential 1 (TRPC1). Neurotransmitter-regulated salivary gland fluid secretion in TRPC1-deficient TRPC1(-/-) mice was severely decreased (by 70%). Further, agonist- and thapsigargin-stimulated SOC channel activity was significantly reduced in salivary gland acinar cells isolated from TRPC1(-/-) mice. Deletion of TRPC1 also eliminated sustained Ca(2+)-dependent potassium channel activity, which depends on Ca(2+) entry and is required for fluid secretion. Expression of key proteins involved in fluid secretion and Ca(2+) signaling, including STIM1 and other TRPC channels, was not altered. Together, these data demonstrate that reduced SOC entry accounts for the severe loss of salivary gland fluid secretion in TRPC1(-/-) mice. Thus, TRPC1 is a critical component of the SOC channel in salivary gland acinar cells and is essential for neurotransmitter-regulation of fluid secretion.     

瞬时受体电位香草酸亚型1通过调节Ca2＋依赖性转录调节因子参与促大鼠血管平滑肌细胞增殖

目的]探讨瞬时受体电位香草酸亚型1(TRPV1)对Ca²＋依赖性转录调节因子表达的影响以及大鼠血管平滑肌细胞(RVSMC)增殖的作用。 [方法]体外培养RVSMC,利用TRPV1特异性激动剂辣椒素(CAP)或抑制剂辣椒卓平(CPZ)促进或抑制TRPV1的表达。免疫细胞化学染色技术检测TRPV1的表达;噻唑蓝法检测细胞增殖活性;Western blot检测增殖细胞核抗原(PCNA)蛋白表达;Western blot和实时荧光定量PCR检测Ca²＋依赖性转录调节因子活化T细胞核因子c1(NFATc1)、钙衰蛋白(CSEN)和肌细胞增强因子2C(MEF2C)的蛋白表达和mRNA水平。 [结果]免疫细胞化学染色显示TRPV1主要表达在RVSMC的胞膜和胞质,CAP或CPZ能激活或抑制TRPV1的表达。与对照组相比,CAP可明显刺激RVSMC增殖活性和上调PCNA蛋白的表达(P＜0.01),同时,NFATc1、MEF2C的蛋白和mRNA水平显著上调(P＜0.01);CSEN蛋白表达显著增高(P＜0.01),CSEN mRNA水平无明显变化(P＞0.05)。CPZ作用后,与对照组比较,RVSMC增殖活性、PCNA蛋白表达降低(P＜0.01),NFATc1、MEF2C的蛋白和mRNA水平显著下调(P＜0.01);CSEN蛋白表达显著降低(P＜0.01),CSEN mRNA水平无明显变化(P＞0.05)。 [结论]TRPV1可能通过上调Ca²＋依赖性转录调节因子的表达参与促RVSMC增殖。     

CaBP1, a neuronal Ca2+ sensor protein,inhibits inositol trisphosphate receptors by clamping intersubunit interactions

Calcium-binding protein 1 (CaBP1) is a neuron-specific member of the calmodulin superfamily that regulates several Ca²⁺ channels, including inositol 1,4,5-trisphosphate receptors (InsP₃Rs). CaBP1 alone does not affect InsP₃R activity, but it inhibits InsP₃-evoked Ca²⁺ release by slowing the rate of InsP₃R opening. The inhibition is enhanced by Ca²⁺ binding to both the InsP₃R and CaBP1. CaBP1 binds via its C lobe to the cytosolic N-terminal region (NT; residues 1–604) of InsP₃R1. NMR paramagnetic relaxation enhancement analysis demonstrates that a cluster of hydrophobic residues (V101, L104, and V162) within the C lobe of CaBP1 that are exposed after Ca²⁺ binding interact with a complementary cluster of hydrophobic residues (L302, I364, and L393) in the β-domain of the InsP₃-binding core. These residues are essential for CaBP1 binding to the NT and for inhibition of InsP₃R activity by CaBP1. Docking analyses and paramagnetic relaxation enhancement structural restraints suggest that CaBP1 forms an extended tetrameric turret attached by the tetrameric NT to the cytosolic vestibule of the InsP₃R pore. InsP₃ activates InsP₃Rs by initiating conformational changes that lead to disruption of an intersubunit interaction between a “hot-spot” loop in the suppressor domain (residues 1–223) and the InsP₃-binding core β-domain. Targeted cross-linking of residues that contribute to this interface show that InsP₃ attenuates cross-linking, whereas CaBP1 promotes it. We conclude that CaBP1 inhibits InsP₃R activity by restricting the intersubunit movements that initiate gating.     

Syntaxin 5 regulates the endoplasmic reticulum channel-release properties of polycystin-2

Polycystin-2 (PC2), the gene product of one of two genes mutated in dominant polycystic kidney disease, is a member of the transient receptor potential cation channel family and can function as intracellular calcium (Ca²⁺) release channel. We performed a yeast two-hybrid screen by using the NH₂ terminus of PC2 and identified syntaxin-5 (Stx5) as a putative interacting partner. Coimmunoprecipitation studies in cell lines and kidney tissues confirmed interaction of PC2 with Stx5 in vivo. In vitro binding assays showed that the interaction between Stx5 and PC2 is direct and defined the respective interaction domains as the t-SNARE region of Stx5 and amino acids 5 to 72 of PC2. Single channel studies showed that interaction with Stx5 specifically reduces PC2 channel activity. Epithelial cells overexpressing mutant PC2 that does not bind Stx5 had increased baseline cytosolic Ca²⁺ levels, decreased endoplasmic reticulum (ER) Ca²⁺ stores, and reduced Ca²⁺ release from ER stores in response to vasopressin stimulation. Cells lacking PC2 altogether had reduced cytosolic Ca²⁺ levels. Our data suggest that PC2 in the ER plays a role in cellular Ca²⁺ homeostasis and that Stx5 functions to inactivate PC2 and prevent leaking of Ca²⁺ from ER stores. Modulation of the PC2/Stx5 interaction may be a useful target for impacting dysregulated intracellular Ca²⁺ signaling associated with polycystic kidney disease.     

Sequential dissection of multiple ionic currents in single cardiac myocytes under action potential-clamp

The cardiac action potential (AP) is shaped by myriad ionic currents. In this study, we develop an innovative AP-clamp Sequential Dissection technique to enable the recording of multiple ionic currents in the single cell under AP-clamp. This new technique presents a significant step beyond the traditional way of recording only one current in any one cell. The ability to measure many currents in a single cell has revealed two hitherto unknown characteristics of the ionic currents in cardiac cells: coordination of currents within a cell and large variation of currents between cells. Hence, the AP-clamp Sequential Dissection method provides a unique and powerful tool for studying individual cell electrophysiology.