突触前受体的药理学研究进展

综述了突触前受体存在的证据、分类、调节和临床意义。突触前受体按不同的分类方法可分为突触前自调受体和旁调受体;抑制性和易化性突触前受体;G-蛋白偶联型和离子通道型突触前受体。突触前受体调节递质释放的机制,可能与钙通道、钾通道及囊泡释放复合物的调节有关。通过研制合适的突触前受体的激动剂或拮抗剂,适度调节神经末梢递质的释放,可达到控制或治疗多种疾病(如高血压、精神疾患、阿尔茨海默病、心肌缺血等)的目的。     

代谢型谷氨酸受体介导的电 化学信号及其生物学作用

<正>大约50年前,就已经发现谷氨酸可以诱发癫痫,并可以直接兴奋哺乳动物神经元。近20年来,药理学研究已经鉴定并克隆出不同类型的谷氨酸门控离子通道,通过激活这些通道,谷氨酸介导快速的突触后电位。20世纪80年代中期,研究者又发现谷氨酸还可以通过产生三磷酸肌醇(IP3)发挥作用,这表明存在着代谢型谷氨酸受体或非离子通道型谷氨酸受体。本文就近年代谢型谷氨酸受体(mGluRs)的结构特征、胞内信号转导机制及生物学作用综述如下。     

N-甲基-D-天冬氨酸-2B受体功能的研究进展

N-甲基-D-天冬氨酸(mDA)受体是一种配体门控型离子通道，由7种亚型(NR1，NR2A，NR2B，NR2C，NR2D，NR3A和NR3B)组成，通过其不同亚型与细胞内多种蛋白相互作用。NR2B受体参与突触信号转导和蛋白之间的调节，与学习、记忆、疼痛感受、进食行为及多种神经疾病有关。本文综述了近年来有关NR2B受体的结构、分布及功能调节等方面的研究进展。     

NMDA型谷氨酸受体NR3亚基与药物依赖相关研究进展

<正>NMDA受体是一类门控离子通道型谷氨酸受体,参与调节中枢神经系统的多种重要功能:如神经元生长发育、神经可塑性及学习记忆等。NMDA受体是异多聚体,由核心亚基NR1结合强化亚基NR2及(或)调节亚基NR3组成。NR1亚基形成离子通道。NR2亚基在配体识别、调控及与其他蛋白相互作用等方面发挥重要作用。和NR1和NR2亚基相比,NR3亚基最晚发现;NR3亚基可形成NR1/NR3     

人参皂苷Rg3与离子通道受体作用的研究进展

目的对人参皂苷Rg3(ginsenoside Rg3,G-Rg3)与离子通道受体作用进行全面总结。方法根据国内外最新有关文献,依据作用的离子通道受体不同进行分类介绍。结果G-Rg3可作用于离子通道受体,通过与特定氨基酸残基的作用,影响离子通道活性,进而影响某些离子的通透性。结论为G-Rg3的药理作用研究提供参考。     

NMDARs转运与突触可塑性及神经精神疾病

N-甲基-D-天冬氨酸受体(NMDARs)是谷氨酸门控离子通道,在调节中枢神经系统突触功能中发挥重要作用.NMDARs是由NR1、NR2和NR3亚基组成的异聚体,具有不同的生理、药理学特性及突触定位方式;这些亚基在内质网中共同翻译组装成有功能的离子通道.     

手性药物作用于离子通道受体的研究进展

离子通道受体是一种膜受体 ,它们分子结构相近 ,拥有特异药物结合位点 ,可分为两种类型。由内源性配体控制的称配体门控离子通道受体 ,由跨膜电位改变控制的称电压门控离子通道受体。离子通道对离子具有精确的选择性或者完全没有区别。因此 ,常把通道看作是选择性滤孔。滤孔上一个或两个氨基酸的改变就足以改变通道的立体选择性。离子通道能一个或多个同时开放 ,有时甚至关闭着还具有活性 ,这些代表着受体的不同状态。药物依据不同的通道状态而起不同的作用 ,反过来这也反映了通道与药物对映异构体间的不同相互作用。本文主要对近年研究的一…     

海葵多肽神经毒素的研究新进展

海葵具有用于捕食和防御功能的触手刺细胞,其分泌的毒液主要包含蛋白和多肽类毒素,其中多肽神经毒素具有序列多样、结构稳定、靶点特异等特点.目前,人们已经从海葵中分离并鉴定了100余种多肽神经毒素,以电压门控钠离子通道、电压门控钾离子通道、酸敏感离子通道等为主要作用靶点,它们已经成为研究特定离子通道的结构和功能的重要工具.综...     

烟碱乙酰胆碱受体结构的研究进展

烟碱型乙酰胆碱受体（nAChR）是离子通道型受体,属于Cys-loop受体的超级家族,通过配体门控离子通道介导许多生理活动,是治疗精神类疾病的重要靶点。nAChR包括肌肉型和神经型两种。nAChR是由五个亚基组成的具有中心孔道的五聚体,本文简要介绍了近年来烟碱乙酰胆碱受体结构的研究进展。     

离子通道的第3类调节方式——G蛋白门控性通道

离子通道的第３类调节方式——Ｇ蛋白门控性通道电压和配基门控离子通道是兴奋性细胞膜上两类主要的离子通道。电压门控离子通道对膜电压变化敏感，如Ｋ＋、Ｎａ＋、Ｃａ２＋通道；配基门控性通道对特异配基敏感，如α心受体、ＧＡＢＡＡ受体及Ｃａ２＋激活的Ｋ＋通道等。...     

An Overview of The Three Dimensional Structure of Short Spider Toxins

Arthropods are one of the most diverse animal groups on the Earth. Spiders belong to this phylum and they are ancient animals with a history going back some three hundred million years. They are abundant, widespread, and natural controllers of insect populations. They use their venom to capture prey or to fight against predators. This venom is constituted of various peptides and enzymes with different activities. Among these proteins, toxic peptides are responsible for the macroscopic effect of the venom.

Most of the toxins are known to interact with ion channels (mainly potassium channels, sodium channels, and calcium channels). These transmembrane molecules are ubiquitous in the cells. They underlie a broad range of the most basic biological processes, from excitation and signaling to secretion and absorption. Like enzymes they are diverse and ubiquitous macromolecular catalysts with high substrate specificity and subject to strong regulation. Animal toxins and, more specifically, spider toxins are effectors of these channels. Depending on the peptide, they have ability to block the channel by plugging into its pore of conduction, or by modifying the opening and closing capacity of the channels, binding on a few specific sites along the structure of the channel.

Most of these peptides fold according to the overall same pattern, the inhibitor cystine knot (ICK) scaffold. Basically, it consists of a ring formed by a part of the backbone of the peptide and two disulfide bridges, penetrated by a third disulfide bridge. An additional disulfide bridge might be found in some toxins. Another fold has been found in a few toxins and has been described as the DDH scaffold. This motif lacks the knot and comprises an antiparallel β -hairpin stabilized by two conserved disulfide bridges.

This paper will try to summarize the structural characteristics of the spider toxins for which the fold has been described in the literature.     

Ion channels in toxicology

Ion channels play essential roles in human physiology and toxicology. Cardiac contraction, neural transmission, temperature sensing, insulin release, regulation of apoptosis, cellular pH and oxidative stress, as well as detection of active compounds from chilli, are some of the processes in which ion channels have an important role. Regulation of ion channels by several chemicals including those found in air, water and soil represents an interesting potential link between environmental pollution and human diseases; for instance, de novo expression of ion channels in response to exposure to carcinogens is being considered as a potential tool for cancer diagnosis and therapy. Non‐specific binding of several drugs to ion channels is responsible for a huge number of undesirable side‐effects, and testing guidelines for several drugs now require ion channel screening for pharmaceutical safety. Animal toxins targeting human ion channels have serious effects on the population and have also provided a remarkable tool to study the molecular structure and function of ion channels. In this review, we will summarize the participation of ion channels in biological processes extensively used in toxicological studies, including cardiac function, apoptosis and cell proliferation. Major findings on the adverse effects of drugs on ion channels as well as the regulation of these proteins by different chemicals, including some pesticides, are also reviewed. Association of ion channels and toxicology in several biological processes strongly suggests these proteins to be excellent candidates to follow the toxic effects of xenobiotics, and as potential early indicators of life‐threatening situations including chronic degenerative diseases. Copyright © 2010 John Wiley & Sons, Ltd.     

Potential therapeutic targets for ATP-gated P2X receptor ion channels

P2X receptors make up a novel family of ligand-gated ion channels that are activated by binding of extracellular ATP. These receptors can form a number of homomeric and heteromeric ion channels, which are widely distributed throughout the human body. They are thought to play an important role in many cellular processes, including synaptic transmission and thrombocyte aggregation. These ion channels are also involved in the pathology of several disease states, including chronic inflammation and neuropathic pain, and thus are the potential targets for drug development. The recent discovery of potent and highly selective antagonists for P2X(7) receptors, through the use of high-throughput screening, has helped to further understand the P2X receptor pharmacology and provided new evidence that P2X(7) receptors play a specific role in chronic pain states. In this review, we discuss how the P2X family of ion channels has distinguished itself as a potential new drug target. We are optimistic that safe and effective candidate drugs will be suitable for progression into clinical development.     

Gastrointestinal afferents as targets of novel drugs for the treatment of functional bowel disorders and visceral pain.

An intricate surveillance network consisting of enteroendocrine cells, immune cells and sensory nerve fibres monitors the luminal and interstitial environment in the alimentary canal. Functional bowel disorders are characterized by persistent alterations in digestive regulation and gastrointestinal discomfort and pain. Visceral hyperalgesia may arise from an exaggerated sensitivity of peripheral afferent nerve fibres and/or a distorted processing and representation of gut signals in the brain. Novel strategies to treat these sensory bowel disorders are therefore targeted at primary afferent nerve fibres. These neurons express a number of molecular traits including transmitters, receptors and ion channels that are specific to them and whose number and/or behaviour may be altered in chronic visceral pain. The targets under consideration comprise vanilloid receptor ion channels, acid-sensing ion channels, sensory neuron-specific Na(+) channels, P2X(3) purinoceptors, 5-hydroxytryptamine (5-HT), 5-HT(3) and 5-HT(4) receptors, cholecystokinin CCK(1) receptors, bradykinin and prostaglandin receptors, glutamate receptors, tachykinin and calcitonin gene-related peptide receptors as well as peripheral opioid and cannabinoid receptors. The utility of sensory neuron-targeting drugs in functional bowel disorders will critically depend on the compounds' selectivity of action for afferent versus enteric or central neurons.     

The Effects of General Anesthetics on Synaptic Transmission

General anesthetics are a class of drugs that target the central nervous system and are widely used for various medical procedures. General anesthetics produce many behavioral changes required for clinical intervention, including amnesia, hypnosis, analgesia, and immobility; while they may also induce side effects like respiration and cardiovascular depressions. Understanding the mechanism of general anesthesia is essential for the development of selective general anesthetics which can preserve wanted pharmacological actions and exclude the side effects and underlying neural toxicities. However, the exact mechanism of how general anesthetics work is still elusive. Various molecular targets have been identified as specific targets for general anesthetics. Among these molecular targets, ion channels are the most principal category, including ligand-gated ionotropic receptors like γ-aminobutyric acid, glutamate and acetylcholine receptors, voltage-gated ion channels like voltage-gated sodium channel, calcium channel and potassium channels, and some second massager coupled channels. For neural functions of the central nervous system, synaptic transmission is the main procedure for which information is transmitted between neurons through brain regions, and intact synaptic function is fundamentally important for almost all the nervous functions, including consciousness, memory, and cognition. Therefore, it is important to understand the effects of general anesthetics on synaptic transmission via modulations of specific ion channels and relevant molecular targets, which can lead to the development of safer general anesthetics with selective actions. The present review will summarize the effects of various general anesthetics on synaptic transmissions and plasticity.     

Emerging molecular mechanisms of general anesthetic action

General anesthetics are essential to modern medicine, and yet a detailed understanding of their mechanisms of action is lacking. General anesthetics were once believed to be "drugs without receptors" but this view has been largely abandoned. During the past decade significant progress in our understanding of the mechanisms of general anesthetic action at the molecular, cellular and neural systems levels has been made. Different molecular targets in various regions of the nervous system are involved in the multiple components of anesthetic action, and these targets can vary between specific anesthetics. Neurotransmitter-gated ion channels, particularly receptors for GABA and glutamate, are modulated by most anesthetics, at both synaptic and extrasynaptic sites, and additional ion channels and receptors are also being recognized as important targets for general anesthetics. In this article, these developments, which have important implications for the development of more-selective anesthetics, are reviewed in the context of recent advances in ion channel structure and function.     

Toxin determinants required for interaction with voltage-gated K channels

Ion channel-acting toxins are mainly short peptides generally present in minute amounts in the venoms of diverse animal species such as scorpions, snakes, spiders, marine cone snails and sea anemones. Interestingly, these peptides have evolved over time on the basis of clearly distinct architectural motifs present throughout the animal kingdom, but display convergent molecular determinants and functional homologies. As a consequence of this conservation of some key determinants, it has also been evidenced that toxin targets display some common evolutionary origins. Indeed, these peptides often target ion channels and ligand-gated receptors, though other interacting molecules such as enzymes have been further evidenced. In this review, we provide an overview of some selected peptides from various animal species that act on specific K⁺ conducting voltage-gated ion channels. In particular, we emphasize our global analysis on the structural determinants of these molecules that are required for the recognition of a particular ion channel pore structure, a property that should be correlated to the blocking efficacy of the K⁺ efflux out of the cell during channel opening. A better understanding of these molecular determinants is valuable to better specify and derive useful peptide pharmacological properties.     

Associated proteins: The universal toolbox controlling ligand gated ion channel function

Ligand gated ion channels are integral multimeric membrane proteins that can detect with high sensitivity the presence of a specific transmitter in the extracellular space and transduce this signal into an ion flux. While these receptors are widely expressed in the nervous system, their expression is not limited to neurons or their postsynaptic targets but extends to non-neuronal cells where they participate in many physiological responses. Cells have developed complex regulatory mechanisms allowing for the precise control and modulation of ligand gated ion channels. In this overview the roles of accessory subunits and associated proteins in these regulatory mechanisms are reviewed and their relevance illustrated by examples at different ligand gated ion channel types, with emphasis on nicotinic acetylcholine receptors. Dysfunction of ligand gated ion channels can result in neuromuscular, neurological or psychiatric disorders. A better understanding of the precise function of associated proteins and how they impact on ligand gated ion channels will provide new therapeutic opportunities for clinical intervention.     

An assessment of the present and future roles of non-ligand gated ion channel modulators as CNS therapeutics

Few approved drugs have, as their primary known mechanism of action, modulation of non-ligand gated ion channels. However, these proteins are important regulators of neuronal function through their control of sodium, potassium, calcium and chloride flux, and are ideal candidates as drug discovery targets. Recent progress in the molecular biology and pharmacology of ion channels suggests that many will be associated with specific pharmacological profiles that will include both activators and inhibitors. Ion channels, through their regulation by G-proteins, are a major component of the final common pathway of many drugs acting at classical neuronal receptors. Thus, targeting of the ion channels themselves may confer different profiles of efficacy and specificity to drug action in the brain and spinal cord. Three areas for drug discovery are profiled that the authors consider prime targets for ion channel based therapies, anticonvulsant drugs, cognition enhancing drugs and drugs for improving neurone survival following ischaemia.     

An assessment of the present and future roles of non-ligand gated ion channel modulators as CNS therapeutics

Few approved drugs have, as their primary known mechanism of action, modulation of non-ligand gated ion channels. However, these proteins are important regulators of neuronal function through their control of sodium, potassium, calcium and chloride flux, and are ideal candidates as drug discovery targets. Recent progress in the molecular biology and pharmacology of ion channels suggests that many will be associated with specific pharmacological profiles that will include both activators and inhibitors. Ion channels, through their regulation by G-proteins, are a major component of the final common pathway of many drugs acting at classical neuronal receptors. Thus, targeting of the ion channels themselves may confer different profiles of efficacy and specificity to drug action in the brain and spinal cord. Three areas for drug discovery are profiled that the authors consider prime targets for ion channel based therapies, anticonvulsant drugs, cognition enhancing drugs and drugs for improving neurone survival following ischaemia.