细胞内镁离子平衡调节机制研究进展

Mg2+是细胞内第二位含量丰富的二价阳离子,与生物体的生理病理变化密切相关,但对其平衡调节的机制还不十分清楚。该文就细胞膜通道TRPM6、TRPM7,转运体Na+/Mg2+交换、Ca2+/Mg2+交换及细胞内ATP、蛋白、线粒体、内质网、细胞核与胞内游离镁离子稳态调节研究进展进行综述以为读者提供一个了解镁离子调节的机会。     

TRPM7 在卵巢癌中的研究进展

TRPM7 也称LTRPC-7（long TRP channel 7），表达于哺乳动物的心、肝、脾、肺、肾、骨骼和消化道等多种组织及器\r\n官中，在细胞内Ca2+、Mg2+ 浓度及细胞行为的调节过程中有重要意义。研究发现，TRPM7 通道在卵巢癌的增殖、侵袭、转移\r\n中也有重要作用，但其机制目前尚不清楚。TRPM7 相关的离子通道研究可能为卵巢癌治疗方案和预后提供新的线索。     

TRPM7在糖尿病心肌纤维化中的作用

糖尿病心肌病（Diabetic cardiomyopathy，DCM）是糖尿病（Diabetes mellitus，DM）恶化到一定阶段后出现的心血管并发症。纤维化是其中重要的病理重构，主要由心脏成纤维细胞（Cardiac fibroblasts，CFs）参与。TRPM7（Transient receptor potential melastatin-subfamily member 7）是一种具有阳离子通道和蛋白激酶双重结构的膜蛋白，组成性表达于心脏成纤维细胞中。TRPM7在糖尿病心肌纤维化的病理过程中发挥着重要作用，能够通过影响转化生长因子β1（Transforming growth factor β1，TGF-β1）的表达、肾素-血管紧张素-醛固酮系统（Renin-angiotensin-aldosterone system，RAAS）的活化、Ca2+的信号转导和Mg2+的代谢，从而影响糖尿病心肌纤维化的发展进程。本文综述TRPM7在糖尿病心肌纤维化中的广泛和重要作用，并关注了其作为减轻纤维发生的治疗靶点的潜力。     

成骨细胞跨膜转运锌特性及其机制的初步研究

目的　研究锌在成骨细胞跨膜转运的动力学特点及影响因素 ,为阐明锌在骨发育中的作用提供科学依据。方法　采用65Zn同位素示踪法研究锌在成骨细胞跨膜转运的动力学特点 ;分别研究组氨酸、Na+、K+泵抑制剂、Ca2 +离子通道阻滞剂对成骨细胞锌转运的影响。结果　细胞外锌浓度增加可以促进锌转运入胞内 ,但锌缺乏使锌胞内转运减少 ;组氨酸、Na+、K+泵抑制剂对锌转运无影响 ;Ca2 +离子通道阻滞剂促进锌内流。结论　成骨细胞外环境锌水平可以影响成骨细胞锌转运及胞内锌水平 ,Ca2 +离子通道与Zn2 +通道可能相互影响     

TRPM7通道在肿瘤发生发展过程中的作用研究进展

瞬时电位受体(transient receptor potential,TRP)melastatin亚家族7(TRPM7)是一种包含功能性激酶结构域的非选择性阳离子通道。研究表明,多种肿瘤细胞中TRPM7异常高表达,可通过诱导细胞周期紊乱、调节细胞内阳离子浓度,促进肿瘤细胞生存与增殖。此外,TRPM7表达升高与肿瘤侵袭、转移能力的增加密切相关,且这种作用可能是通过促进上皮细胞-间充质转化及肿瘤血管生成产生的。TRPM7在肿瘤发生发展中的作用,使其成为恶性肿瘤的预后指标和潜在治疗靶点。该文对TRPM7与肿瘤进程的研究进展进行综述,探讨TRPM7介导肿瘤发展的机制及靶向TRPM7的临床治疗肿瘤策略,为后续研究和临床治疗提供一定参考。     

瞬时受体电位8型的功能结构及其化学调节剂的研究进展

瞬时受体电位8型(transient receptor potential melastatin-related 8，TRPM8)是一种非选择性钙离子通道，其功能异常或缺失会导致多种疾病。TRPM8参与生物体的体温调节、肿瘤、炎症、疼痛和哮喘等生理及病理活动，特别是在肿瘤治疗过程中，TRPM8常被用作治疗的潜在靶点。大部分化学调节剂是通过影响细胞内Ca²⁺浓度平衡来激活TRPM8通道。本文对TRPM8通道的结构、功能及其对不同疾病的调节作用等进行归纳及分析，为TRPM8作为临床治疗及新药开发靶点提供借鉴。     

水通道AQP1的研究进展

水通道蛋白是水分子通过生物膜脂质双分子层的一种膜蛋白,在动植物尤其在哺乳动物体内被发现并得到鉴定。AQP1（aquaporin1）是水通道蛋白家族中最早被发现的一个亚型,对水的转运有高度选择性。现已发现,AQP1分布在多种器官组织中,特别是那些与液体吸收和分泌有关的上皮细胞及可能协同水跨细胞转运的内皮细胞中,参与水的跨膜转运及水平衡调节。研究AQP1对于了解水代谢疾病的发生机制以及指导临床水代谢疾病的治疗具有十分重要的意义。     

肺水通道蛋白的研究进展

水通道蛋白(aquaporin,AQPS)是新近发现的一组与水通透性有关的细胞膜转运蛋白,是一种可调节进出细胞膜的水通道同源蛋白质家族的总称,它的发现在分子水平上揭示了水跨膜转运的调节机制。AQPS在维持肺脏的液体平衡中起着重要的作用。本文就肺AQPS的研究进展做一综述。1AQPS的结构1988年Agre发现了整合膜蛋白28(CH 1P28)后命名为水     

缺血性脑损伤与瞬时受体电位M通道的研究进展

缺血性脑血管病是临床常见病、多发病,其发病机制复杂。钙超载在缺血性脑损伤中起重要作用。瞬时受体电位M通道(transient receptor potential melastatin,TRPM)是位于细胞膜上的一类重要的非选择性阳离子通道超家族,对钙离子有较高的通透性,在缺血性脑损伤中起重要作用,对TRPM通道的研究将成为治疗缺血性脑损伤新的靶点。本文就胞内钙离子超载在缺血性脑损伤中的作用、TRPM通道及其参与的缺血性脑损伤的机制予以综述。     

水通道蛋白8与胎膜水平衡调控相关性研究进展

水通道蛋白（AQP）是一类对水具有高度选择性的跨膜糖蛋白，可介导自由水快速被动跨生物膜转运，是水分子跨膜转运的主要分子基础，对保持细胞内外环境的稳态起重要作用，同时参与机体一些重要的生理功能。自1988年Agre分离出第一个AQP以来，目前已确定了13种AQP家族成员，即AQP0、AQP1～12，称为AQP家族（AQPS）。迄今为止，AQP的基因结构和表达调控、染色体定位、蛋白结构、组织分布和生理功能均得到了一定的研究。近年来有关胎膜与AQPS的研究只涉及AQP1、3、4、8、9。水通道蛋白8作为一种重要的调控哺乳动物胎膜两侧水平衡的跨膜通道蛋白目前广受关注。     

The TRPM ion channel subfamily: molecular, biophysical and functional features

Significant progress in the molecular and functional characterization of a subfamily of genes that encode melastatin-related transient receptor potential (TRPM) cation channels has been made during the past few years. This subgroup of the TRP superfamily of ion channels contains eight mammalian members and has isoforms in most eukaryotic organisms. The individual members of the TRPM subfamily have specific expression patterns and ion selectivity, and their specific gating and regulatory mechanisms are tailored to integrate multiple signaling pathways. The diverse functional properties of these channels have a profound effect on the regulation of ion homoeostasis by mediating direct influx of Ca2+, controlling Mg2+ entry, and determining the potential of the cell membrane. TRPM channels are involved in several physiological and pathological conditions in electrically excitable and non-excitable cells, which make them exciting targets for drug discovery.     

TRP channels in lymphocytes

TRP proteins form ion channels that are activated following receptor stimulation. Several members of the TRP family are likely to be expressed in lymphocytes. However, in many studies, messenger RNA (mRNA) but not protein expression was analyzed and cell lines but not primary human or murine lymphocytes were used. Among the expressed TRP mRNAs are TRPC1, TRPC3, TRPM2, TRPM4, TRPM7, TRPV1, and TRPV2. Regulation of Ca2+ entry is a key process for lymphocyte activation, and TRP channels may both increase Ca2+ influx (such as TRPC3) or decrease Ca2+ influx through membrane depolarization (such as TRPM4). In the future, linking endogenous Ca2+/cation channels in lymphocytes with TRP proteins should lead to a better molecular understanding of lymphocyte activation.     

Emerging functions of 10 types of TRP cationic channel in vascular smooth muscle

1. The influx of Ca2+, Mg2+ and Na+ and the efflux of K+ have central importance for the function and survival of vascular smooth muscle cells, but progress in understanding the influx/efflux pathways has been restricted by a lack of identification of the genes underlying many of the non-voltage-gated cationic channels. 2. The present review highlights evidence suggesting the genes are mammalian homologues of the Transient Receptor Potential (TRP) gene of the fruit-fly Drosophila. The weight of evidence supports roles for TRPC1, TRPP2/1 and TRPC6, but recent studies point also to TRPC3, TRPC4/5, TRPV2, TRPM4 and TRPM7. 3. Activity of these TRP channels is suggested to modulate contraction and sense changes in intracellular Ca2+ storage, G-protein-coupled receptor activation and osmotic stress. Roles in relation to myogenic tone, actions of vasoconstrictors substances, Mg2+ homeostasis and the vascular injury response are suggested. 4. Knowledge that TRP channels are relevant to vascular smooth muscle cells in both their contractile and proliferative phenotypes should pave the way for a better understanding of vascular biology and provide the basis for the discovery of a new set of therapeutic agents targeted to vascular disease.     

N-(p-amylcinnamoyl)anthranilic acid (ACA): a phospholipase A(2) inhibitor and TRP channel blocker

Phospholipase A(2) enzymes display a superfamily of structurally different enzymes classified in at least nine subfamilies by biochemical and structural properties. N-(p-amylcinnamoyl)anthranilic acid commonly referred to as ACA is often used as a broad-spectrum inhibitor for the characterization of phospholipase A(2)-mediated pathways. Compounds like ACA and ACA-like structures have been described to block the receptor-induced release of arachidonic acid and subsequent signaling cascades in the pancreas and the cardiovascular system. We showed that ACA directly blocks several transient receptor potential (TRP) channels (TRPC6, TRPM2, TRP and TRPM8). With respect to the published data of ACA in the phospholipase A(2) field, the finding that ACA blocks diacylglycerol-activated TRP channels is of specific interest as it offers the opportunity to interfere with receptor-induced calcium-dependent signaling processes in platelets and vascular smooth muscle cells. Overall, N-phenylcinnamides, as a new pharmaceutical lead structure, form the first class of synthetic TRP channel blockers and represent a promising start for the development of small organic TRP channel-specific blockers.     

TRP channels in neurogastroenterology: opportunities for therapeutic intervention

The members of the superfamily of transient receptor potential (TRP) cation channels are involved in a plethora of cellular functions. During the last decade, a vast amount of evidence is accumulating that attributes an important role to these cation channels in different regulatory aspects of the alimentary tract. In this review we discuss the expression patterns and roles of TRP channels in the regulation of gastrointestinal motility, enteric nervous system signalling and visceral sensation, and provide our perspectives on pharmacological targeting of TRPs as a strategy to treat various gastrointestinal disorders. We found that the current knowledge about the role of some members of the TRP superfamily in neurogastroenterology is rather limited, whereas the function of other TRP channels, especially of those implicated in smooth muscle cell contractility (TRPC4, TRPC6), visceral sensitivity and hypersensitivity (TRPV1, TRPV4, TRPA1), tends to be well established. Compared with expression data, mechanistic information about TRP channels in intestinal pacemaking (TRPC4, TRPC6, TRPM7), enteric nervous system signalling (TRPCs) and enteroendocrine cells (TRPM5) is lacking. It is clear that several different TRP channels play important roles in the cellular apparatus that controls gastrointestinal function. They are involved in the regulation of gastrointestinal motility and absorption, visceral sensation and visceral hypersensitivity. TRP channels can be considered as interesting targets to tackle digestive diseases, motility disorders and visceral pain. At present, TRPV1 antagonists are under development for the treatment of heartburn and visceral hypersensitivity, but interference with other TRP channels is also tempting. However, their role in gastrointestinal pathophysiology first needs to be further elucidated.     

Activation of the melastatin-related cation channel TRPM3 by D-erythro-sphingosine [corrected

TRPM3, a member of the melastatin-like transient receptor potential channel subfamily (TRPM), is predominantly expressed in human kidney and brain. TRPM3 mediates spontaneous Ca2+ entry and nonselective cation currents in transiently transfected human embryonic kidney 293 cells. Using measurements with the Ca2+-sensitive fluorescent dye fura-2 and the whole-cell patch-clamp technique, we found that D-erythro-sphingosine, a metabolite arising during the de novo synthesis of cellular sphingolipids, activated TRPM3. Other transient receptor potential (TRP) channels tested [classic or canonical TRP (TRPC3, TRPC4, TRPC5), vanilloid-like TRP (TRPV4, TRPV5, TRPV6), and melastatin-like TRP (TRPM2)] did not significantly respond to application of sphingosine. Sphingosine-induced TRPM3 activation was not mediated by inhibition of protein kinase C, depletion of intracellular Ca2+ stores, and intracellular conversion of sphingosine to sphingosine-1-phosphate. Although sphingosine-1-phosphate and ceramides had no effect, two structural analogs of sphingosine, dihydro-D-erythro-sphingosine and N,N-dimethyl-D-erythro-sphingosine, also activated TRPM3. Sphingolipids, including sphingosine, are known to have inhibitory effects on a variety of ion channels. Thus, TRPM3 is the first ion channel activated by sphingolipids.     

The Mg2+ and Mg(2+)-nucleotide-regulated channel-kinase TRPM7

TRPM7 is a member of the melastatin-related subfamily of TRP channels and represents a protein that contains both an ion channel and a kinase domain. The protein is ubiquitously expressed and represents the only ion channel known that is essential for cellular viability. TRPM7 is a divalent cation-selective ion channel that is permeable to Ca2+ and Mg2+, but also conducts essential metals such as Zn2+, Mn2+, and Co2+, as well as nonphysiologic or toxic metals such as Ni2+, Cd2+, Ba2+, and Sr2+. The channel is constitutively open but strongly downregulated by intracellular levels of Mg2+ and MgATP and other Mg-nucleotides. Reducing the cellular levels of these regulators leads to activation of TRPM7-mediated currents that exhibit a characteristic nonlinear current-voltage relationship with pronounced outward rectification due to divalent influx at physiologically negative voltages and monovalent outward fluxes at positive voltages. TRPM7 channel activity is also actively regulated following receptor-mediated changes in cyclic AMP (cAMP) and protein kinase A activity. This regulation as well as that by Mg-nucleotides requires a functional endogenous kinase domain. The function of the kinase domain is not completely understood, but may involve autophosphorylation of TRPM7 as well as phosphorylation of other target proteins such as annexin and myosin IIA heavy chain. Based on these properties, TRPM7 is currently believed to represent a ubiquitous homeostatic mechanism that regulates Ca2+ and Mg2+ fluxes based on the metabolic state of the cell. Physiologically, the channel may serve as a regulated transport mechanism for these ions that could affect cell adhesion, cell growth and proliferation, and even cell death under pathological stress such as anoxia.     

Oncogenic role and therapeutic target of transient receptor potential melastatin 7 channel in malignancy

Introduction: The transient receptor potential (TRP) family is a superfamily of cation channels which regulates many features of malignant cancers, such as lack of differentiation, increased migratory and invasive phenotype and chemoresistance. The TRP cation channel, TRPM7 (subfamily M, member 7), is a ubiquitous, Ca²⁺ and Mg²⁺-permeant ion channel that is unique in that it is an ion channel and a serine/threonine kinase. TRPM7 has been associated with cell proliferation, survival and development and thus correlated with growth and progression of several types of tumor cells, including breast cancer, gastric cancer, head and neck cancer, nasopharyngeal carcinoma, pancreatic cancer, prostate cancer, retinoblastoma and leukemia. Increased TRPM7 expression in human breast and pancreatic cancer tissues also correlates with clinicopathological parameters, such as tumor grade, the Ki-67 proliferation index and patient survival.

Areas covered: In this review, we focus on recent advancements in knowledge of aberrant TRPM7 channel function and its contribution to tumor progression and angiogenesis. This includes crosstalk between multiple signaling pathways. The role of TRPM7 in tumor development, particularly in regard to its channel function mediating both Ca²⁺ and Mg²⁺ influx as well as its kinase activity is also addressed. In addition, we will discuss its role in the stem cell and cancer stem cell, as well as its potential as tumor drug target.

Expert opinion: Better understanding of the structure, function and regulation of TRPM7 channel, as well as its complex crosstalk with other oncogenic signals in tumor cells will be essential to ensure rational use of treatment and development of new combinatory therapeutic possibilities.     

Ethanol’s Effects on Transient Receptor Potential Channel Expression in Brain Microvascular Endothelial Cells

Ethanol (EtOH), the main ingredient in alcoholic beverages, is well known for its behavioral, physiological, and immunosuppressive effects. There is evidence that EtOH acts through protein targets to exert its physiological effects; however, the mechanisms underlying EtOH’s effects on inflammatory processes, particularly at the blood-brain barrier (BBB), are still poorly understood. Transient receptor potential (TRP) channels, the vanguards of human sensory systems, are novel molecular receptors significantly affected by EtOH, and are heavily expressed in brain microvascular endothelial cells (BMVECs), one of the cellular constituents of the BBB. EtOH’s actions on endothelial TRP channels could affect intracellular Ca²⁺ and Mg²⁺ dynamics, which mediate leukocyte adhesion to endothelial cells and endothelial permeability at the BBB, thus altering immune and inflammatory responses. We examined the basal expression profiles of all 29 known mammalian TRP channels in mouse BMVECs and determined both EtOH concentration- and time-dependent effects on TRP expression using a PCR array. We also generated an in vitro BBB model to examine the involvement of a chosen TRP channel, TRP melastatin 7 (TRPM7), in EtOH-mediated alteration of BBB permeability. With the exception of the akyrin subfamily, members of five TRP subfamilies were expressed in mouse BMVECs, and their expression levels were modulated by EtOH in a concentration-dependent manner. In the in vitro BBB model, TRPM7 antagonists further enhanced EtOH-mediated alteration of BBB permeability. Because of the diversity of TRP channels in BMVECs that regulate cellular processes, EtOH can affect Ca²⁺/Mg²⁺ signaling, immune responses, lysosomal functions as well as BBB integrity.