TRP通道与信号转导

TRP(transient receptor potential)通道是一类在外周和中枢神经系统分布很广泛的通道蛋白.到目前为止,有超过30个TRP通道家族成员在哺乳动物中被克隆.TRP通道均为六次跨膜蛋白,其N末端和C末端均在胞内,由第五和第六跨膜结构域共同构成非选择性阳离子孔道.这些通道可被许多种因素调节,包括温度、渗透压、pH值、机械力,以及一些内、外源性配体和细胞内信号分子.TRP通道家族包含七个亚族.目前,它们最公认的功能是介导感觉信号的传递,其他功能包括调节细胞钙平衡和影响发育等.     

瞬时受体电位通道与心肌肥大研究进展

瞬时受体电位(transient receptor potential, TRP)通道家族是一类广泛分布于人体各组织和器官的阳离子通道。近年来研究发现,部分表达于心肌细胞的TRP通道亚家族成员在病理性心肌肥大中发挥重要作用,目前关于TRP通道与心肌肥大研究的大量实验结果提示,TRP通道有可能成为干预病理性心肌肥大的重要靶点,TRP通道在病理性心肌肥大中的作用和机制成为一个研究热点。本文主要对参与病理性心肌肥大的TRP通道及其可能机制的最新进展进行综述。     

瞬时受体电位通道在心脑血管系统疾病中的研究进展

瞬时受体电位(TRP)通道是一类重要的非选择性阳离子通道,其家族成员众多,参与多种生理病理过程。其中,TRP通道的异常表达及功能改变与心脑血管疾病的发生发展密切相关。近年研究发现,通过拮抗或者激活TRP通道可以调节血管内皮和血管平滑肌功能,参与心脑血管疾病的调控。该文主要从TRP通道的结构及各亚家族蛋白基于血管内皮和血管平滑肌对心脑血管系统疾病的作用及机制作一综述,为心脑血管疾病的防治提供新思路。     

瞬时受体电位通道研究进展

瞬时受体电位通道(TRP channels)是位于细胞膜上的一类重要的阳离子通道超家族.根据氨基酸序列的同源性,将已发现的28种哺乳动物,TRP通道分为:TRPC、TRPV、TRPM、TRPA、TRPP和TRPML 6个亚家族.所有的TRP通道都具有6次跨膜结构域.不同的TRP通道对钙离子和钠离子选择性不同.TRP通道分布广泛,调节机制各异,通过感受细胞内外环境的各种刺激,参与痛温觉、机械感觉、味觉的发生和维持细胞内外环境的离子稳态等众多生命活动.     

翻译后修饰调控TRPV亚家族通道功能的研究进展

瞬时受体势(transient receptor potential,TRP)通道广泛分布于神经和非神经系统中,响应温度、化学和机械等多种刺激,在机体对外界环境的精确感知中发挥重要功能.根据蛋白质序列的相似性,哺乳动物中TRP通道家族的27个成员分属TRPA、TRPC、TRPM、TRPML、TRPP和TRPV 6个亚家...     

科研人员揭示TRPC通道保护小脑神经元存活的研究新成果

神经元的存活对神经系统发育、神经系统疾病发生及发展都十分重要。TRP通道是一类非选择性的阳离子通道,可以影响从痛觉到雄性生殖等多方面的生理功能。TRPC通道是TRP通道的一个亚家族,可被与磷脂酶C偶联的受体（如脑源性神经生长因子BDNF）激活。     

瞬时感受器电位Ⅴ亚家族离子通道——温度感受器

生物体可以感受广泛的温度范围,其中温度超过43℃或低于15℃还可引起伤害性痛觉。近年来在哺乳动物中已经发现6个与温度有关的通道,其中4个属于瞬时感受器电位（transient receptor potential,TRP）Ⅴ亚家族成员。这些通道组织分布非常广泛,功能上属于钙渗透性通道,可被多种理化刺激激活。它们具有不同的温度阈值,并受一些理化因素的调节。     

我国科学家发现TRPC通道新功能

突触的形成对建立神经网络十分重要。突触形成是一个复杂的过程。TRP通道是一类6次跨膜的非选择性阳离子通道。它们在进化中高度保守,在哺乳动物体内广泛表达,参与了许多重要的生理学功能,如对温度、痛觉、听觉的感知以及受精。TRPC通道是TRP的一个亚家族,在人的中枢神经系统中表达丰富,但人们对其生理功能却知之较少。     

TRPC6通道促进兴奋性突触的形成，提高小鼠空间学习和记忆能力

突触的形成对建立神经网络十分重要。突触形成是一个复杂的过程。TRP通道是一类六次跨膜的非选择性阳离子通道。它们在进化中高度保守,在哺乳动物体内广泛表达,参与了许多重要的生理学功能,如对温度、痛觉、听觉的感知以及受精。TRPC通道是TRP的一个亚家族,在人的中枢神经系统中表达丰富,但其生理功能却知之较少。     

瞬时受体电位通道的结构研究进展

瞬时受体电位(transient receptor potential,TRP)通道是一类由多个成员构成的非选择性阳离子通道大家族,在机体感受外界环境变化和多种刺激中发挥重要的作用。过去的10年间,TRP通道的结构生物学研究取得了重大的进展。到目前为止,共有5个TRP通道的全长结构和11个胞内段的结构得到了解析。这些结构的解析加深了我们对TRP通道的门控、组装和调节等机制的理解。本文对这些TRP通道的结构进行综述并针对近两年取得的进展做重点的介绍。     

Structural Pharmacology of TRP Channels

Transient receptor potential (TRP) ion channels are a super-family of ion channels that mediate transmembrane cation flux with polymodal activation, ranging from chemical to physical stimuli. Furthermore, due to their ubiquitous expression and role in human diseases, they serve as potential pharmacological targets. Advances in cryo-EM TRP channel structural biology has revealed general, as well as diverse, architectural elements and regulatory sites among TRP channel subfamilies. Here, we review the endogenous and pharmacological ligand-binding sites of TRP channels and their regulatory mechanisms.     

Heteromerization of TRP channel subunits: extending functional diversity

Transient receptor potential (TRP) channels are widely found throughout the animal kingdom. By serving as cellular sensors for a wide spectrum of physical and chemical stimuli, they play crucial physiological roles ranging from sensory transduction to cell cycle modulation. TRP channels are tetrameric protein complexes. While most TRP subunits can form functional homomeric channels, heteromerization of TRP channel subunits of either the same subfamily or different subfamilies has been widely observed. Heteromeric TRP channels exhibit many novel properties compared to their homomeric counterparts, indicating that co-assembly of TRP channel subunits has an important contribution to the diversity of TRP channel functions.     

Open channel block by Ca2+ underlies the voltage dependence of drosophila TRPL channel

The light-activated channels of Drosophila photoreceptors transient receptor potential (TRP) and TRP-like (TRPL) show voltage-dependent conductance during illumination. Recent studies implied that mammalian members of the TRP family, which belong to the TRPV and TRPM subfamilies, are intrinsically voltage-gated channels. However, it is unclear whether the Drosophila TRPs, which belong to the TRPC subfamily, share the same voltage-dependent gating mechanism. Exploring the voltage dependence of Drosophila TRPL expressed in S2 cells, we found that the voltage dependence of this channel is not an intrinsic property since it became linear upon removal of divalent cations. We further found that Ca(2+) blocked TRPL in a voltage-dependent manner by an open channel block mechanism, which determines the frequency of channel openings and constitutes the sole parameter that underlies its voltage dependence. Whole cell recordings from a Drosophila mutant expressing only TRPL indicated that Ca(2+) block also accounts for the voltage dependence of the native TRPL channels. The open channel block by Ca(2+) that we characterized is a useful mechanism to improve the signal to noise ratio of the response to intense light when virtually all the large conductance TRPL channels are blocked and only the low conductance TRP channels with lower Ca(2+) affinity are active.     

A Novel Ion Channel Formed by Interaction of TRPML3 with TRPV5

TRPML3 and TRPV5 are members of the mucolipin (TRPML) and TRPV subfamilies of transient receptor potential (TRP) cation channels. Based on sequence similarities of the pore forming regions and on structure-function evidence, we hypothesized that the pore forming domains of TRPML and TRPV5/TRPV6 channels have similarities that indicate possible functional interactions between these TRP channel subfamilies. Here we show that TRPML3 and TRPV5 associate to form a novel heteromeric ion channel. This novel conductance is detectable under conditions that do not activate either TRPML3 or TRPV5. It has pharmacological similarity with TRPML3 and requires functional TRPML3 as well as functional TRPV5. Single channel analyses revealed that TRPML3 and TRPV5 heteromers have different features than the respective homomers, and furthermore, that they occur in potentially distinct stoichiometric configurations. Based on overlapping expression of TRPML3 and TRPV5 in the kidney and the inner ear, we propose that TRPML3 and TRPV5 heteromers could have a biological function in these organs.     

Genetic strategies to analyze primary TRP channel-expressing cells in mice

Transient receptor potential (TRP) ion channels regulate fundamental biological processes throughout the body. TRP channel dysfunction has been causally linked to a number of disease states and thus establishes these channels as promising therapeutic targets. In order to dissect the physiological role of individual TRP channels in specific tissues, a detailed understanding of the expression pattern of the different TRP channels throughout the organism is essential. We provide an overview of recent efforts to generate novel TRP channel reporter mouse strains for all 28 TRP channels encoded in the mouse genome to understand expression of these channels with a single-cell resolution in an organism-wide manner. The reporter mice will enable both the visualization and manipulation of all primary TRP channel-expressing cells allowing an unprecedented wealth in variety to investigate TRP channel function in vivo. As proof of principle, we provide preliminary results documenting TRPM5 expression throughout the entire body of juvenile and adult mice.     

A comparison of the genes coding for canonical TRP channels and their M,V and P relatives

The mammalian transient receptor potential (TRP) protein gene family consists of a diverse group of cation channels that currently contain at least 26 members. The physiologic functions of many remain unknown. They are structurally similar to Drosophila TRP and have a wide tissue distribution. In the present report, we compare the chromosomal locations, the gene, and primary structures of each of these 26 human TRP family members. Based on primary amino acid analyses, these channels comprise four different subfamilies: C- (canonical or classical), V- (or vanilloid receptor related), M- (melastatin related), and P (PKD)-type. The highest homology within each subfamily and between subfamilies exists in the predicted ion channel domains. Belonging to a given subfamily, however, does not determine the activating stimuli. This is exemplified by the V- and M-subfamilies, both of which have members that respond to temperature and osmolarity. TRP genes vary in their intron-exon organization, with the greatest diversity in the P subfamily. Chromosomal organization analyses revealed that two TRP members are found as direct repeats; TRPV3 follows TRPV1 and TRPV6 follows TRPV5. Both of these duplications appear to be recent as TRPV1 and V3 are more similar to each other than to other members of the TRPV subfamily. The same holds true for TRPV5 and V6. The article presents complication of comparisons including exon-intron boundaries, the amino acid sequence alignments, and the chromosomal organization of each of the presently known TRP channels.     

Unstructural Biology of TRP Ion Channels: The Role of Intrinsically Disordered Regions in Channel Function and Regulation

The first genuine high-resolution single particle cryo-electron microscopy structure of a membrane protein determined was a transient receptor potential (TRP) ion channel, TRPV1, in 2013. This methodical breakthrough opened up a whole new world for structural biology and ion channel aficionados alike. TRP channels capture the imagination due to the sheer endless number of tasks they carry out in all aspects of animal physiology. To date, structures of at least one representative member of each of the six mammalian TRP channel subfamilies as well as of a few non-mammalian families have been determined. These structures were instrumental for a better understanding of TRP channel function and regulation. However, all of the TRP channel structures solved so far are incomplete since they miss important information about highly flexible regions found mostly in the channel N- and C-termini. These intrinsically disordered regions (IDRs) can represent between a quarter to almost half of the entire protein sequence and act as important recruitment hubs for lipids and regulatory proteins. Here, we analyze the currently available TRP channel structures with regard to the extent of these “missing” regions and compare these findings to disorder predictions. We discuss select examples of intra- and intermolecular crosstalk of TRP channel IDRs with proteins and lipids as well as the effect of splicing and post-translational modifications, to illuminate their importance for channel function and to complement the prevalently discussed structural biology of these versatile and fascinating proteins with their equally relevant ’unstructural’ biology.     

TRP channels: an overview

The TRP ("transient receptor potential") family of ion channels now comprises more than 30 cation channels, most of which are permeable for Ca2+, and some also for Mg2+. On the basis of sequence homology, the TRP family can be divided in seven main subfamilies: the TRPC ('Canonical') family, the TRPV ('Vanilloid') family, the TRPM ('Melastatin') family, the TRPP ('Polycystin') family, the TRPML ('Mucolipin') family, the TRPA ('Ankyrin') family, and the TRPN ('NOMPC') family. The cloning and characterization of members of this cation channel family has exploded during recent years, leading to a plethora of data on the roles of TRPs in a variety of tissues and species, including mammals, insects, and yeast. The present review summarizes the most pertinent recent evidence regarding the structural and functional properties of TRP channels, focusing on the regulation and physiology of mammalian TRPs.     

Chemical physiology of oxidative stress-activated TRPM2 and TRPC5 channels

The ability to sense and adapt to a wide variety of environmental changes is crucial for the survival of all cells. Transient receptor potential (TRP) channels play pivotal roles in these sensing and adaptation reactions. In vertebrates, there are about 30 TRP channels; these are divided into six subfamilies by homology of the protein sequences. We have previously revealed that a group of TRP channels senses oxidative stress and induces cellular signaling and gene expression. TRPM2, a member of the TRPM subfamily, is activated by reactive oxygen species (ROS) via second-messenger production. Recently, we demonstrated that Ca²⁺ influx through TRPM2 activated by ROS induces chemokine production in monocytes, which aggravates inflammatory neutrophil infiltration. Additionally, we also revealed that nitric oxide, chemical compounds containing reactive disulfide, and inflammatory mediators directly activate the TRPC, TRPV, and TRPA subfamilies via oxidative modification of cysteine residues. In this review, we describe how these TRP channels sense oxidative stress and induce adaptation reactions, and we discuss the biological importance of oxidative stress-activated TRP channels.