TRPV1阻断剂的研究进展

瞬时感受器电位香草酸受体1(TRPV1)是瞬时感受器电位（transient receptor potential,TRP)的非选择性阳离子通道蛋白家族成员之一，主要表达在初级传入感觉神经元上，是一种非选择性的阳离子通道。该受体可探测和整合诱发痛觉的化学和热刺激信号，主要有辣椒素（红辣椒的辛辣成分），伤害性热（>43℃）和质子等。它可将化学、机械和热刺激信号转化为动作电位，并将这些信息上传到中枢，最后使机体产生痛觉或不舒服的感受。近年来，TRPV1通道蛋白已成为开发新的镇痛药物的重要靶点。     

TRPV1 抗炎保护功能的研究新进展

<正>瞬时感受器电位香草酸受体(Transient receptor potential vanilloid,TRPV1)属于瞬时受体电位(TRP)超家族重要成员之一,是一类主要位于细胞膜上的重要的非选择性阳离子通道,在TRPV亚族中,TRPV1与炎性疼痛的形成关系最为密切~([1])。研究表明,TRPV1是感觉神经介导某些伤害性刺激的分子整合器,与炎性疼痛的产生关系密切,多种神经炎症介质和内源性介质(SP、PG及NGF等)均可直接或间接激活TRPV1~([2])。TRPV1被激活后,会使胞     

TRPC通道参与疼痛信号传递过程与作用机制的研究进展

<正>瞬时受体电位通道(transient receptor potential,TRP)家族是一类六次跨膜的非选择性阳离子通道,主要包括TRPC、TRPA、TRPM、TRPV、TRPP和TRPML六个亚家族。近年来越来越多的实验证据表明TRP通道是痛觉信息传递系统的"前沿哨兵",响应细胞及机体内外伤害性热、冷、机械和化学等刺激,并将其转换为动作电位向脊髓及上位脑中枢传递最终产生痛感觉~([1,2])。其中哺乳动物TRPC通道家族的七个成员     

TRPV4在心血管疾病中作用的研究进展

<正>瞬时受体电位阳离子通道V亚家族成员4(tran-sientreceptorpotentialcationchannelsubfamilyV member4,TRPV4)是瞬时受体电位阳离子通道(transient receptor potential cation channel, TRP)家族成员，是一种非选择性阳离子通道，对Ca²⁺离子具有适中通透性，对Na⁺和Mg²⁺少量通透(P_Ca/P_Na约为6～10,P_Ca/P_Mg约为2～3)。TRPV4在心血管系统表达广泛，主要表达于血管内皮细胞、血管平滑肌细胞、心肌细胞和成纤维细胞等，可调节血管张力和血管通透性，参与机械信号传导等。     

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。     

TRPV1在脑的表达模式

<正>TRPV1(transient receptor potential vanilloid type-1,瞬时受体电位香草素亚型1)是一种钙离子高通透性的非选择性阳离子通道。它是香草素瞬时受体电位家族的成员,其开始被定义为是辣椒有效成分--辣椒素的受体(Caterina等,1997)。TRPV1是一种多形性的瞬时受体电位通道,它能够被伤害性热、酸碱度改变、脂肪酸酰胺以及内源性脂质配体     

TRPM家族对细胞钙/镁平衡调控的研究进展

TRPM通道是TRP通道超家族的一员.包括TRPM1至TRPM8八个成员,除TRPM4与TRPM5外,其余成员对Ca2+和Mg2+均具有一定通透性.其中TRPM1、TRPM2、TRPM3和TRPM8主要参与调控细胞Ca2+的平衡,而TRPM6和TRPM7是调控细胞Mg2+平衡的关键通道.TRPM家族成员分布广泛,调节机制各异,对于细胞钙/镁平衡等一系列生理功能具有重要调控作用.     

TRPM7与乳腺癌的研究进展

瞬时受体电位(transient receptor potential,TRP)通道是一种非选择性阳离子通道超级家族.作为TRPM亚家族的一员,TRPM7因其独特的丝氨酸/苏氨酸激酶结构、广泛的分布以及多样的生理功能而引起了关注.众多研究结果表明:TRPM7通道的表达或功能异常与乳腺癌的发生及发展密切相关.目前,转移性乳腺癌不可被治愈,是导致乳腺癌患者死亡的主要原因.     

温度敏感TRP通道:从2021年诺贝尔生理学或医学奖的温度感知机制的发现到心血管和代谢的调控

2021年诺贝尔生理学或医学奖授予辣椒素受体TRPV1和薄荷醇感受器TRPM8通道的突破性发现，丰富了人们对热和冷触发的神经感知，及其适应环境温度机制的认识。温度敏感TRP通道——“热通道”TRPV1和“冷通道”TRPM8 不仅在神经系统有丰富表达，也存在于心血管、脂肪、肝脏和肌肉等组织器官，但其生物学意义并不清楚。为此，国内外学者探索温度敏感TRP通道调控心血管功能及糖脂代谢的作用，及其激动剂辣椒素和薄荷醇对心血管及代谢病的治疗效益。 2021年的诺贝尔奖使这个相对冷门的领域引起了较高的关注，并将推动其他多个领域的发展。     

机械感觉相关的TRP通道研究进展

瞬时受体电位通道(transient receptor potential channels,TRP channels)是一类六次跨膜的非选择性阳离子通道,与经典离子通道主要受膜电位或配体的激活不同,TRP通道可受渗透压、pH值、机械力、配体以及细胞内信号分子等多种因素的激活,进而参与体内多种生理和病理过程,如感受痛、热等伤害刺激以及参与炎症等病理过程。近来较多的证据提示TRP通道在机械感觉中尤其有重要作用。本文对机械感觉功能相关的TRP通道,尤其是与听觉相关的TRP通道的研究进展进行综述,分析可能的激活和调控机制并展望其未来的发展方向。     

A single N-terminal cysteine in TRPV1 determines activation by pungent compounds from onion and garlic

Some members of the transient receptor potential (TRP) family of cation channels mediate sensory responses to irritant substances. Although it is well known that TRPA1 channels are activated by pungent compounds found in garlic, onion, mustard and cinnamon extracts, activation of TRPV1 by these extracts remains controversial. Here we establish that TRPV1 is activated by pungent extracts from onion and garlic, as well as by allicin, the active compound in these preparations, and participates together with TRPA1 in the pain-related behavior induced by this compound. We found that in TRPV1 these agents act by covalent modification of cysteine residues. In contrast to TRPA1 channels, modification of a single cysteine located in the N-terminal region of TRPV1 was necessary and sufficient for all the effects we observed. Our findings point to a conserved mechanism of activation in TRP channels, which provides new insights into the molecular basis of noxious stimuli detection.     

Expression of transient receptor potential (TRP) channel mRNAs in the mouse olfactory bulb

Transient receptor potential (TRP) channels are a large family of cation channels. The 28 TRP channel subtypes in rodent are divided into 6 subfamilies: TRPC1-7, TRPV1-6, TRPM1-8, TRPP2/3/5, TRPML1-3 and TRPA1. TRP channels are involved in peripheral olfactory transduction. Several TRPC channels are expressed in unidentified neurons in the main olfactory bulb (OB), but the expression of most TRP channels in the OB has not been investigated. The present study employed RT-PCR as an initial survey of the expression of TRP channel mRNAs in the mouse OB and in 3 cell types: external tufted, mitral and granule cells. All TRP channel mRNAs except TRPV5 were detected in OB tissue. Single cell RT-PCR revealed that external tufted, mitral and granule cell populations expressed in aggregate 14 TRP channel mRNAs encompassing members of all 6 subfamilies. These different OB neuron populations expressed 7–12 channel mRNAs. Common channel expression was more similar among external tufted and mitral cells than among these cells and granule cells. These results indicate that a large number of TRP channel subtypes are expressed in OB neurons, providing the molecular bases for these channels to regulate OB neuron activity and central olfactory processing.     

Role of TRPV ion channels in sensory transduction of osmotic stimuli in mammals

In signal transduction of metazoan cells, ion channels of the family of transient receptor potential (TRP) have been identified to respond to diverse external and internal stimuli, amongst them osmotic stimuli. This report highlights findings pertaining to the TRPV subfamily, focusing on mammalian members. Of the six mammalian TRPV channels, TRPV1, 2 and 4 were demonstrated to function in transduction of osmotic stimuli. TRPV channels have been found to function in cellular as well as systemic osmotic homeostasis. In a striking example of evolutionary conservation of function, mammalian TRPV4 has been found to rescue osmosensory deficits of the TRPV mutant strain osm-9 in Caenorhabditis elegans, despite not more than 26% orthology of the respective proteins.     

Renoprotection: focus on TRPV1, TRPV4, TRPC6 and TRPM2

Members of the transient receptor potential (TRP) cation channel receptor family have unique sites of regulatory function in the kidney which enables them to promote regional vasodilatation and controlled Ca²⁺ influx into podocytes and tubular cells. Activated TRP vanilloid 1 receptor channels (TRPV1) have been found to elicit renoprotection in rodent models of acute kidney injury following ischaemia/reperfusion. Transient receptor potential cation channel, subfamily C, member 6 (TRPC6) in podocytes is involved in chronic proteinuric kidney disease, particularly in focal segmental glomerulosclerosis (FSGS). TRP vanilloid 4 receptor channels (TRPV4) are highly expressed in the kidney, where they induce Ca²⁺ influx into endothelial and tubular cells. TRP melastatin (TRPM2) non‐selective cation channels are expressed in the cytoplasm and intracellular organelles, where their inhibition ameliorates ischaemic renal pathology. Although some of their basic properties have been recently identified, the renovascular role of TRPV1, TRPV4, TRPC6 and TRPM2 channels in disease states such as obesity, hypertension and diabetes is largely unknown. In this review, we discuss recent evidence for TRPV1, TRPV4, TRPC6 and TRPM2 serving as potential targets for acute and chronic renoprotection in chronic vascular and metabolic disease.     

Function and regulation of TRP family channels in C. elegans

Seventeen transient receptor potential (TRP) family proteins are encoded by the C. elegans genome, and they cover all of the seven TRP subfamilies, including TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML. Classical forward and reverse genetic screens have isolated mutant alleles in every C. elegans trp gene, and their characterizations have revealed novel functions and regulatory mechanisms of TRP channels. For example, the TRPC channels TRP-1 and TRP-2 control nicotine-dependent behavior, while TRP-3, a sperm TRPC channel, is regulated by sperm activation and required for sperm–egg interactions during fertilization. Similar to their vertebrate counterparts, C. elegans TRPs function in sensory physiology. For instance, the TRPV channels OSM-9 and OCR-2 act in chemosensation, osmosensation, and touch sensation, the TRPA member TRPA-1 regulates touch sensation, while the TRPN channel TRP-4 mediates proprioception. Some C. elegans TRPM, TRPP, and TRPML members exhibit cellular functions similar to their vertebrate homologues and have provided insights into human diseases, including polycystic kidney disease, hypomagnesemia, and mucolipidosis type IV. The availability of a complete set of trp gene mutants in conjunction with its facile genetics makes C. elegans a powerful model for studying the function and regulation of TRP family channels in vivo.     

PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain

The subjective feeling of cold is mediated by the activation of TRPM8 channels in thermoreceptive neurons by cold or by cooling agents such as menthol. Here, we demonstrate a central role for phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) in the activation of recombinant TRPM8 channels by both cold and menthol. Moreover, we show that Ca(2+) influx through these channels activates a Ca(2+)-sensitive phospholipase C and that the subsequent depletion of PI(4,5)P(2) limits channel activity, serving as a unique mechanism for desensitization of TRPM8 channels. Finally, we find that mutation of conserved positive residues in the highly conserved proximal C-terminal TRP domain of TRPM8 and two other family members, TRPM5 and TRPV5, reduces the sensitivity of the channels for PI(4,5)P(2) and increases inhibition by PI(4,5)P(2) depletion. These data suggest that the TRP domain of these channels may serve as a PI(4,5)P(2)-interacting site and that regulation by PI(4,5)P(2) is a common feature of members of the TRP channel family.     

Gating of TRP channels: a voltage connection?

TRP channels represent the main pathways for cation influx in non-excitable cells. Although TRP channels were for a long time considered to be voltage independent, several TRP channels now appear to be weakly voltage dependent with an activation curve extending mainly into the non-physiological positive voltage range. In connection with this voltage dependence, there is now abundant evidence that physical stimuli, such as temperature (TRPV1, TRPM8, TRPV3), or the binding of various ligands (TRPV1, TRPV3, TRPM8, TRPM4), shift this voltage dependence towards physiologically relevant potentials, a mechanism that may represent the main functional hallmark of these TRP channels. This review discusses some features of voltage-dependent gating of TRPV1, TRPM4 and TRPM8. A thermodynamic principle is elaborated, which predicts that the small gating charge of TRP channels is a crucial factor for the large voltage shifts induced by various stimuli. Some structural considerations will be given indicating that, although the voltage sensor is not yet known, the C-terminus may substantially change the voltage dependence of these channels.     

Epithelial calcium channels: from identification to function and regulation

The epithelial calcium channels TRPV5 and TRPV6 have been studied extensively in the epithelial tissues controlling Ca(2+) homeostasis and exhibit a range of distinctive properties that distinguish them from other transient receptor potential (TRP) channels. These two novel members of the superfamily of TRP channels were cloned from vitamin D-responsive epithelia: kidney, small intestine and placenta, and identified subsequently in tissues like pancreas, bone and prostate. This review addresses the unique properties of these highly Ca(2+)-selective channels and highlights their implications for the process of transepithelial Ca(2+) transport.     

Transient receptor potential channels in bladder function

The transient receptor potential (TRP) superfamily of cationic ion channels includes proteins involved in the transduction of several physical and chemical stimuli to finely tune physiological functions. In the urinary bladder, they are highly expressed in, but not restricted to, primary afferent neurons. The urothelium and some interstitial cells also express several TRP channels. In this review, we describe the expression and the known roles of some members of TRP subfamilies, namely TRPV, TRPM and TRPA, in the urinary bladder. The therapeutic interest of modulating the activity of TRP channels to treat bladder dysfunctions is also discussed.     

Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity

The transient receptor potential (TRP) ion channel family was the last major ion channel family to be discovered. The prototypical member (dTRP) was identified by a forward genetic approach in Drosophila , where it represents the transduction channel in the photoreceptors, activated downstream of a Gq-coupled PLC. In the meantime 29 vertebrate TRP isoforms are recognized, distributed amongst seven subfamilies (TRPC, TRPV, TRPM, TRPML, TRPP, TRPA, TRPN). They subserve a wide range of functions throughout the body, most notably, though by no means exclusively, in sensory transduction and in vascular smooth muscle. However, their precise physiological roles and mechanism of activation and regulation are still only gradually being revealed. Most TRP channels are subject to multiple modes of regulation, but a common theme amongst the TRPC/V/M subfamilies is their regulation by lipid messengers. Genetic evidence supports an excitatory role of diacylglycerol (DAG) for the dTRP's, although curiously only DAG metabolites (PUFAs) have been found to activate the Drosophila channels. TRPC2,3,6 and 7 are widely accepted as DAG-activated channels, although TRPC3 can also be regulated via a store-operated mechanism. More recently PIP₂ has been shown to be required for activity of TRPV5, TRPM4,5,7 and 8, whilst it may inhibit TRPV1 and the dTRPs. Although compelling evidence for a direct interaction of DAG with the TRPC channels is lacking, mutagenesis studies have identified putative PIP₂-interacting domains in the C-termini of several TRPV and TRPM channels.