TRPM7生理病理学功能及其小分子调节剂的发现

TRPM7（transient receptor potential melastatin 7）通道属于TRPM亚家族，是一种具有离子通道结构域和激酶结构域的双功能跨膜蛋白。作为非选择性阳离子通道，TRPM7可通透Ca²⁺、Mg²⁺、Zn²⁺、Na⁺、K⁺等和其他微量金属离子。TRPM7在人体各组织广泛表达，参与Mg²⁺的稳态调控、细胞增殖、分化、黏附和迁移等生理过程。临床上，TRPM7功能紊乱与神经退行性疾病、中风、癌症等多种疾病关系密切。本文主要综述TRPM7通道在生理、病理及小分子调节剂方面的研究进展，为相关疾病的药物开发提供新的思路。     

瞬时受体电位M8离子通道功能及其翻译后修饰调节机制

瞬时受体电位M8(transient receptor potential melastatin 8, TRPM8)又称冷及薄荷醇感受器,位于细胞膜或细胞器膜上,是瞬时受体电位(transient receptor potential, TRP)通道超家族中的一员。TRPM8通道分布广泛,是一个非选择性阳离子通道,可作为冷热传感器和冷痛传感器进行信号传导,参与众多生物过程的调节,在维持细胞内外稳态、控制离子进出细胞方面具有重要作用。研究发现,蛋白质翻译后修饰(post-translational modification, PTM)通过调控TRPM8通道的功能,进而影响多种疾病的发生和发展。因此,探究TRPM8的翻译后修饰的过程,对深入了解TRPM8的功能及调控机制是十分必要的。目前,已报道的TRPM8翻译后修饰包括磷酸化、泛素化和糖基化等,它们能够调控蛋白质的相互作用和改变TRPM8离子通道的活性,从而调控细胞增殖、迁移和凋亡。值得注意的是,TRPM8的表达与前列腺癌、膀胱癌和乳腺癌等多种癌症密切相关。本文将从TRPM8离子通道的结构出发,系统地阐述TRPM8蛋白翻译后修饰和激动剂、拮抗剂以及一些蛋白质对TRPM8通道活性的调节,同时总结TRPM8在前列腺癌、膀胱癌和乳腺癌中的新进展,为癌症治疗提供新方向和新思路。     

TRPM2:氧化应激敏感的多功能离子通道(英文)

瞬时受体电位(transient receptor potential,TRP)超家族是一组非选择性阳离子通道,分为7个亚家族。TRPM亚家族包括8个不同的成员,TRPM1~8。TRPM2广泛表达于可兴奋细胞和非兴奋性细胞,形成Ca2+通透性阳离子通道,并发挥不同的细胞功能。TRPM2通道可被ADP-核糖(ADPR)、Ca2+、H2O2以及其他活性氧(ROS)所激活。现已证明,TRPM2作为氧化应激传感器,介导了氧化应激引起的细胞内Ca2+浓度升高,并参与多种细胞的生理/病理过程。丰富的证据表明,TRPM2可作为氧化应激相关疾病的一个潜在的治疗靶点。本文对以上方面的研究进展做一综述。     

心律失常发生的核受体调控机制研究进展

心律失常是一种心脏电活动起源或者转导障碍导致的心脏疾病,其发生发展的分子机制尚不明确。心肌细胞表面膜离子通道与缝隙连接通道蛋白的表达及功能关键性地决定了心脏电活动的稳态。核受体家族(nuclear receptor family)是一组配体激活的转录因子家族,配件包括固醇类激素、维生素D、甲状腺激素等。它们定位于细胞核,在离子通道和缝隙连接蛋白的转录、转运和功能调节中发挥重要的作用。现就近年来核受体调控心律失常发生发展的相关报道做一综述。     

瞬时感受器电位通道与疾病

哺乳动物瞬时感受器电位(transient receptor potential,TRP)通道超家族由TRPC、TRPM、TRPV、TRPA、TRPP和TRPML六个亚家族组成。这些亚家族的29个离子通道几乎表达于所有的组织和细胞。大多对单价和二价阳离子都有通透性。TRP通道与多种生物学功能有关,包括高血压、温度觉、血管炎症、刺激感、肿瘤增生、细胞内离子稳态及神经细胞信号转导。对这些通道的生理功能及其与人类疾病的关系的研究有助于开发具有潜在治疗价值的TRP通道调节剂。     

溶酶体离子通道蛋白在神经退行性疾病发生发展中的作用及机制研究

溶酶体离子通道蛋白异常引起溶酶体功能障碍是导致阿尔茨海默病(Alzheimer’s disease,AD)和帕金森病(Parkinson’s disease,PD)等神经退行性疾病的重要因素.溶酶体离子通道蛋白调节溶酶体内离子稳态、溶酶体膜电压以及溶酶体的酸度.溶酶体离子通道蛋白的结构或功能缺陷会引起溶酶体降解功能障碍,导致神经退行性疾病的发生发展.在这篇综述中,我们总结了各种离子通道蛋白调节溶酶体功能的过程及机制,以及离子通道蛋白异常参与神经退行性疾病的过程和机制.调节离子通道蛋白改善溶酶体的功能、促进异常聚集蛋白的清除,是神经退行性疾病治疗的潜在途径.     

TULP家族成员的生物学功能及相关疾病的致病机制

哺乳动物TULP家族成员包含TUB、TULP1、TULP2、TULP3和TULP4共五种，它们在哺乳动物多种组织中表达，与个体的生长发育、稳态维系、遗传及基因突变所致疾病关系密切。近年来对TULP家族成员的生物学功能及其与疾病的相关性已进行了深入的研究，如TUB所致肥胖-听力减退-视网膜三联征；TULP1的视觉功能与相关眼病治疗方法的探索及评估改进；TULP3除了在胚胎神经发育中的作用及其突变可致纤毛病多囊肾外，更成为相关肿瘤调控的研究热点；TULP4被证明与遗传所致畸形及阿尔茨海默症有关，同时因成为多种疾病的候选基因而受到广泛关注；而TULP2在雄性生殖中的作用也得到了初步的揭示。本文对TULP家族成员在哺乳动物中的生物学功能及其变异所致疾病的发病机制进行了综述，以期为相关疾病的诊断和治疗提供理论依据。     

TRPM7:一种具有离子通道和激酶活性的双功能膜蛋白

TRPM7(transient receptor potential melastatin 7)是近年来发现的一种具有离子通道和蛋白激酶双重结构的双功能蛋白.作为一种非选择性阳离子通道,其对包括Ca2+、Mg2+、K+、Na+在内的众多二价和单价阳离子有通透性;作为一种蛋白激酶其可使自身或底物磷酸化.TRPM7广泛存在于机体组织中,组成性表达于可兴奋和非可兴奋性细胞的质膜上;参与细胞内Mg2+平衡的调节、神经递质的释放、细胞的黏附和迁移等重要生理过程;并成为一些疾病如脑缺血损伤的新的治疗靶点.本文归纳近年的研究,对其结构、调控与功能进行综述.     

一类新型的作用于钾离子通道的蝎毒素多肽

一类新型的作用于钾离子通道的蝎毒素多肽吉永华,刘艳（中国科学院上海生理研究所上海２０００３１）根据Ｋ＋通道的生理和药理特征,它们构成了迄今离子通道研究中一组种类和功能最繁多的蛋白家族。这些通道在诸如肌肉的收缩、神经的分泌、动作电位的频率与延续、体内电...     

瞬时受体电位通道M2在恶性肿瘤中的作用

瞬时受体电位通道M2(transient receptor potential channel melastatin 2, TRPM2)是人体中一个重要的Ca²⁺通透性非选择性阳离子通道,通常表达于正常细胞胞膜和溶酶体膜上,并在氧化应激中发挥重要的离子调节作用。但近年发现,TRPM2也在多种恶性肿瘤(神经母细胞瘤,舌/喉鳞状细胞癌,肺癌,乳腺癌,胃癌,胰腺癌,膀胱癌,前列腺癌和T细胞白血病)中高表达,能通过调节细胞线粒体功能和自噬促进肿瘤细胞的生物学能量而促进其生存能力,通过调节抗氧化物水平增强细胞对氧化刺激的耐受力而表现出化疗抵抗作用。同时,在肿瘤细胞膜上该通道大量激活又对化疗药物联合使用发挥协同作用。此外,TRPM2能通过激活多种不同的分子的信号通路,促进细胞增殖、侵袭和转移能力。总之,根据肿瘤的不同,TRPM2对肿瘤细胞生物学行为的调控机制也不同,甚至具有复杂的双重作用。所以,对TRPM2的生化及分子机制的研究必将使我们对肿瘤的发生发展的认识更加全面。本文将从TRPM2蛋白质的结构,生理功能及肿瘤机制等不同角度系统阐述TRPM2的研究现状和进展。     

Oxidative stress-modulated TRPM ion channels in cell dysfunction and pathological conditions in humans

The transient receptor potential melastatin (TRPM) protein family is an extensive group of ion channels expressed in several types of mammalian cells. Many studies have shown that these channels are crucial for performing several physiological functions. Additionally, a large body of evidence indicates that these channels are also involved in numerous human diseases, known as channelopathies.A characteristic event frequently observed during pathological states is the raising in intracellular oxidative agents over reducing molecules, shifting the redox balance and inducing oxidative stress. In particular, three members of the TRPM subfamily, TRPM2, TRPM4 and TRPM7, share the remarkable feature that their activities are modulated by oxidative stress.Because of the increase in oxidative stress, these TRPM channels function aberrantly, promoting the onset and development of diseases.Increases, absences, or modifications in the function of these redox-modulated TRPM channels are associated with cell dysfunction and human pathologies. Therefore, the effect of oxidative stress on ion channels becomes an essential part of the pathogenic mechanism. Thus, oxidative stress-modulated ion channels are more susceptible to generating pathological states than oxidant-independent channels.This review examines the most relevant findings regarding the participation of the oxidative stress-modulated TRPM ion channels, TRPM2, TRPM4, and TRPM7, in human diseases. In addition, the potential roles of these channels as therapeutic tools and targets for drug design are discussed.     

Emerging structural biology of TRPM subfamily channels

TRPM family (Transient receptor potential channels, M for melastatin) is a group of intrinsic plasma membrane ion channels which are widely expressed throughout human body. It has been identified as a potent entry point of working desperate diseases out in a new way with newfangled ideas and safer technological means. In our review, we discussed the common and unique properties of TRPM family with the elaborate narrate in their overall structures, different states and the underlying activation mechanism. Thus, this review can help to consummate the limited work of TRPM family and provide novel therapeutic targets of certain diseases.     

TRPM7 and its role in neurodegenerative diseases

Calcium (Ca²⁺) and magnesium (Mg²⁺) ions have been shown to play an important role in regulating various neuronal functions. In the present review we focus on the emerging role of transient potential melastatin-7 (TRPM7) channel in not only regulating Ca²⁺ and Mg²⁺ homeostasis necessary for biological functions, but also how alterations in TRPM7 function/expression could induce neurodegeneration. Although eight TRPM channels have been identified, the channel properties, mode of activation, and physiological responses of various TRPM channels are quite distinct. Among the known 8 TRPM channels only TRPM6 and TRPM7 channels are highly permeable to both Ca²⁺ and Mg²⁺; however here we will only focus on TRPM7 as unlike TRPM6, TRPM7 channels are abundantly expressed in neuronal cells. Importantly, the discrepancy in TRPM7 channel function and expression leads to various neuronal diseases such as Alzheimer disease (AD) and Parkinson disease (PD). Further, it is emerging as a key factor in anoxic neuronal death and in other neurodegenerative disorders. Thus, by understanding the precise involvement of the TRPM7 channels in different neurodegenerative diseases and by understanding the factors that regulate TRPM7 channels, we could uncover new strategies in the future that could evolve as new drug therapeutic targets for effective treatment of these neurodegenerative diseases.     

TRPM7 and its role in neurodegenerative diseases

Calcium (Ca²⁺) and magnesium (Mg²⁺) ions have been shown to play an important role in regulating various neuronal functions. In the present review we focus on the emerging role of transient potential melastatin-7 (TRPM7) channel in not only regulating Ca²⁺ and Mg²⁺ homeostasis necessary for biological functions, but also how alterations in TRPM7 function/expression could induce neurodegeneration. Although eight TRPM channels have been identified, the channel properties, mode of activation, and physiological responses of various TRPM channels are quite distinct. Among the known 8 TRPM channels only TRPM6 and TRPM7 channels are highly permeable to both Ca²⁺ and Mg²⁺; however here we will only focus on TRPM7 as unlike TRPM6, TRPM7 channels are abundantly expressed in neuronal cells. Importantly, the discrepancy in TRPM7 channel function and expression leads to various neuronal diseases such as Alzheimer disease (AD) and Parkinson disease (PD). Further, it is emerging as a key factor in anoxic neuronal death and in other neurodegenerative disorders. Thus, by understanding the precise involvement of the TRPM7 channels in different neurodegenerative diseases and by understanding the factors that regulate TRPM7 channels, we could uncover new strategies in the future that could evolve as new drug therapeutic targets for effective treatment of these neurodegenerative diseases.     

TRPM channels, calcium and redox sensors during innate immune responses

Melastatin-related TRPM ion channels have emerged as novel therapeutic targets due to their potential ability to modulate the function and fate of immune cells during inflammation, innate, and adaptive immunity. Four family members, TRPM1, TRPM2, TRPM4 and TRPM7 have a strong presence in the immune system. TRPM channels regulate ion-homeostasis by sensing cellular redox status and cytoplasmic calcium levels. TRPM2 for example, is highly expressed in phagocytes. This channel is activated by intracellular ADP-ribose upon exposure to oxidative stress and induces cell death. Here we will review the functional links between TRPM-mediated ion conductance, chemotaxis, apoptosis, and innate immunity.     

TRPM7 and TRPM2-Candidate susceptibility genes for Western Pacific ALS and PD?

Recent findings implicating TRPM7 and TRPM2 in oxidative stress-induced neuronal death thrust these channels into the spotlight as possible therapeutic targets for neurodegenerative diseases. In this review, we describe how the functional properties of TRPM7 and TRPM2 are interconnected with calcium (Ca(2+)) and magnesium (Mg(2+)) homeostasis, oxidative stress, mitochondrial dysfunction, and immune mechanisms, all principal suspects in neurodegeneration. We focus our discussion on Western Pacific Amyotrophic Lateral Sclerosis (ALS) and Parkinsonism Dementia (PD) because extensive studies conducted over the years strongly suggest that these diseases are ideal candidates for a gene-environment model of etiology. The unique mineral environment identified in connection with Western Pacific ALS and PD, low Mg(2+) and Ca(2+), yet high in transition metals, creates a condition that could affect the proper function of these two channels.     

TRP channels in kidney disease

Mammalian TRP channel proteins form six-transmembrane cation-permeable channels that may be grouped into six subfamilies on the basis of amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML). Recent studies of TRP channels indicate that they are involved in numerous fundamental cell functions and are considered to play an important role in the pathophysiology of many diseases. Many TRPs are expressed in kidney along different parts of the nephron and growing evidence suggest that these channels are involved in hereditary, as well as acquired kidney disorders. TRPC6, TRPM6, and TRPP2 have been implicated in hereditary focal segmental glomerulosclerosis (FSGS), hypomagnesemia with secondary hypocalcemia (HSH), and polycystic kidney disease (PKD), respectively. In addition, the highly Ca(2+)-selective channel, TRPV5, contributes to several acquired mineral (dys)regulation, such as diabetes mellitus (DM), acid-base disorders, diuretics, immunosuppressant agents, and vitamin D analogues-associated Ca(2+) imbalance whereas TRPV4 may function as an osmoreceptor in kidney and participate in the regulation of sodium and water balance. This review presents an overview of the current knowledge concerning the distribution of TRP channels in kidney and their possible roles in renal physiology and kidney diseases.     

Alternative splicing switches the divalent cation selectivity of TRPM3 channels

TRPM3 is a poorly understood member of the large family of transient receptor potential (TRP) ion channels. Here we describe five novel splice variants of TRPM3, TRPM3alpha1-5. These variants are characterized by a previously unknown amino terminus of 61 residues. The differences between the five variants arise through splice events at three different sites. One of these splice sites might be located in the pore region of the channel as indicated by sequence alignment with other, better-characterized TRP channels. We selected two splice variants, TRPM3alpha1 and TRPM3alpha2, that differ only in this presumed pore region and analyzed their biophysical characteristics after heterologous expression in human embryonic kidney 293 cells. TRPM3alpha1 as well as TRPM3alpha2 induced a novel, outwardly rectifying cationic conductance that was tightly regulated by intracellular Mg(2+). However, these two variants are highly different in their ionic selectivity. Whereas TRPM3alpha1-encoded channels are poorly permeable for divalent cations, TRPM3alpha2-encoded channels are well permeated by Ca(2+) and Mg(2+). Additionally, we found that currents through TRPM3alpha2 are blocked by extracellular monovalent cations, whereas currents through TRPM3alpha1 are not. These differences unambiguously show that TRPM3 proteins constitute a pore-forming channel subunit and localize the position of the ion-conducting pore within the TRPM3 protein. Although the ionic selectivity of ion channels has traditionally been regarded as rather constant for a given channel-encoding gene, our results show that alternative splicing can be a mechanism to produce channels with very different selectivity profiles.     

Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels

TRPM2 is a member of the transient receptor potential melastatin-related (TRPM) family of cation channels, which possesses both ion channel and ADP-ribose hydrolase functions. TRPM2 has been shown to gate in response to oxidative and nitrosative stresses, but the mechanism through which TRPM2 gating is induced by these types of stimuli is not clear. Here we show through structure-guided mutagenesis that TRPM2 gating by ADP-ribose and both oxidative and nitrosative stresses requires an intact ADP-ribose binding cleft in the C-terminal nudix domain. We also show that oxidative/nitrosative stress-induced gating can be inhibited by pharmacological reagents predicted to inhibit NAD hydrolysis to ADP-ribose and by suppression of ADP-ribose accumulation by cytosolic or mitochondrial overexpression of an enzyme that specifically hydrolyzes ADP-ribose. Overall, our data are most consistent with a model of oxidative and nitrosative stress-induced TRPM2 activation in which mitochondria are induced to produce free ADP-ribose and release it to the cytosol, where its subsequent accumulation induces TRPM2 gating via interaction within a binding cleft in the C-terminal NUDT9-H domain of TRPM2.