Eph家族蛋白研究进展

Eph家族蛋白包括Eph受体和Ephrin配体,是蛋白酪氨酸激酶家族中的最大成员。由于其具有独特的受体-配体复合物的结构特点及其受体与配体间特有的相互作用模式,所以它们极有可能成为疾病治疗的药物靶标,故该蛋白家族的相关领域研究日益受到重视。该文首先从Eph家族蛋白的分类、表达特点、结构和受体-配体相互作用特点以及其在神经系统中的功能等几个方面简要综述了其相关领域的最新研究进展,进而从结构、作用模式、功能几方面对Eph家族蛋白在神经系统疾患防治中的潜在价值和未来的研究方向进行了探讨和展望。     

G蛋白偶联受体的二聚化及其意义

G蛋白偶联受体(G protein couple receptors,GPCRs)是一个超大的膜受体家族,可以被不同的配体所激活,如激素、多肽、氨基酸、光粒子等。通过与这些配体结合,它们可以介导许多的信号传导,通过激活细胞内的G蛋白,从而激活不同的细胞内通路,产生不同的生物学效应。在对GPCRs的研究初期,普遍认为它们是以单体形式存在并发挥作用的,但后来大量证据表明,绝大多数GPCRs存在二聚化甚至更高的聚合形式,并以此形成基本的功能单位。二聚化可以发生在同受体、相似家族受体或不同家族受体分子之间,其作用可以体现在受体信号传导通路中的诸多环节,如与配体的结合、受体的激活、失敏及运输等。     

PPARγ激动剂荧光探针法研究进展

过氧化物酶增殖激活受体(peroxisome proliferatoractivated receptors,PPARs)属于核激素受体家族中的配体激活受体,包括3种亚型:PPARα、PPARβ/δ和PPARγ。PPARγ具有增强机体对胰岛素敏感性,调节体内糖平衡以及脂肪分化、生成等多种生物学功能。通过荧光探针法研究PPARγ与配体结合,对研究PPARγ激动剂作用机制及筛选PPARγ激动剂具有重要的意义。本文针对新型荧光探针法探究PPARγ与配体的结合能力以及筛选PPARγ激动剂研究进行综述。     

肿瘤坏死因子受体（TNFR）超家族三聚体

肿瘤坏死因子受体（TNFR）超家族的信号转导系统依赖于三聚配体复合物结构的形成，该复合物能激活受体，引起系列生化反应。复合物中几种TNF家族成员与其同源受体的结构表明，每种三聚配体与三种单体受体链相互作用。近期有文章分别报道了利用小分子激动剂和拮抗剂靶向作用于TNFR超家族成员的一种新方法。     

孤啡肽和阿片类配体与阿片孤儿受体相互作用的机制研究(英文)

目的:研究孤啡肽和阿片类配体与阿片孤儿受体相 互作用的分子机制。方法:用分子动力学方法计算孤啡肽的最低能构象;通过分子对接程序将孤啡肽、阿片类配体对接到阿片孤儿受体的结合口袋中;通过结合能的计算研究配体对受体的亲和力与它们的结合能之间的关系。结果:孤啡肽(1-4)残基位于结合口袋的底部,孤啡肽(5-7)残基位于结合口袋的顶部,孤啡肽(8-17)残基与孤儿受体的第二膜外环区结合;阿片类配体和孤儿受体的结合方式与孤啡肽的情况类似,区别在于孤儿受体参与配体结合的残基种类和数量不同,因而亲和力不同;配体-受体的结合能与配体的亲和力之间有很好的相关性;预测了洛芬太尼四个异构体与阿片孤儿受体的亲和力。结论:该研究能够解释许多实验事实,有助于进一步理解阿片受体与配体相互作用的分子机制并设计新的分子生物学实验。     

维甲酸类化合物和维甲酸受体功能研究进展

新的维甲酸类化合物不断开发 ,对维甲酸类化合物诱导细胞分化、凋亡和调节细胞增生的分子机制研究以及在治疗与维甲酸受体发挥主要作用的相关疾病中新思路的开拓具有深远的影响。现将维甲酸类化合物和维甲酸受体功能研究进展作一综述。1　核受体子家族—两类维甲酸受体维甲酸受体属于核受体超家族中的一个子家族 ,在这个超家族中还包括甾体类、维生素 D和甲状腺激素受体及过氧化物酶体增殖物激活受体、昆虫脱皮类固醇受体和许多尚未知其配体的孤儿受体 [1 ] 。维甲酸受体子家族包括两类受体 RARs(retinoic acid receptors)和 RXRs(retino…     

配体诱导受体酪氨酸激酶活化的结构基础研究进展

受体酪氨酸激酶(RTK)家族是一类具有内源性蛋白酪氨酸激酶(PTK)活性的单次跨膜膜受体。它们在调控与细胞增殖、分化等相关的信号转导通路中起关键作用。它与配体结合后引起二聚化或结构重排而使胞内区的酪氨酸(Tyr)被自磷酸化、Try的自磷酸化一方面可以激活胞内PTK区的活性，另一方面可以为下游的信号蛋白提供结合位点从而完成活化过程。本文对RTK家族成员的晶体结构及其活性调节机制的研究进行了综述，阐述了由配体诱导RTK活化的结构基础，并简要讨论了RTK抑制剂可能的作用靶点。     

过氧化物酶体增殖因子活化受体(PPARs)激动剂治疗Ⅱ型糖尿病的研究进展

过氧化物酶体增殖因子活化受体(peroxisome proliferator-activated receptor,PPARs)是核激素受体家族中配体激活受体,主要影响糖尿病的靶蛋白,可以调控葡萄糖、胆固醇及脂代谢紊乱。本文综述了PPARs的结构、分类及其功能,并对单一受体激动剂及PPARα/γ双重激动剂研究进展进行综述。     

表皮生长因子受体酪氨酸激酶家族与肿瘤治疗

表皮生长因子受体(EGFR,ErbB)酪氨酸激酶家族在多种肿瘤中有表达或高表达.在特异性配体的诱导下能够发生家族成员的二聚化,从而激活细胞内下游信号转导途径,调控细胞的增殖、分化、迁移等生物效应.异常的ErbB受体信号与肿瘤的发生、发展有着密切的关系.随着EGFR的人源化单抗Erbitux和针对EGFR的小分子抑制剂Tarceva的成功上市,以ErbB受体为靶点的抗肿瘤药物成为了近年来肿瘤治疗研究中的热点领域.     

PPARγ与骨量丢失

过氧化物酶增值活化受体(peroxisome proliferator-activated receptor,PPAR)家族是一类和甲状腺激素和维甲酸受体密切相关的核受体家族,具有PPARα、PPARβ、PPARγ 3种亚型,其配体为过氧化物体增殖剂、前列腺素代谢物和胰岛素增敏剂等.PPARs不同亚型在体内不同器官的分布及功能也不尽一致.     

Characterization of the Mas-related gene family: structural and functional conservation of human and rhesus MrgX receptors

Recently, a large family of G-protein-coupled receptors called Mas-related genes (Mrgs), which is selectively expressed in small-diameter sensory neurons of dorsal root ganglia, was described. A subgroup of human Mrg receptors (MrgX1-X4) is not found in rodents and this has hampered efforts to define the physiological roles of these receptors. MrgX receptors were cloned from rhesus monkey and functionally characterized alongside their human orthologs. Most of the human and rhesus MrgX receptors displayed high constitutive activity in a cellular proliferation assay. Proliferative responses mediated by human or rhesus MrgX1, or rhesus MrgX2 were partially blocked by pertussis toxin (PTX). Proliferative responses mediated by rhesus MrgX3 and both human and rhesus MrgX4 were PTX insensitive. These results indicate that human and rhesus MrgX1 and MrgX2 receptors activate both Gq- and Gi-regulated pathways, while MrgX3 and MrgX4 receptors primarily stimulate Gq-regulated pathways. Peptides known to activate human MrgX1 and MrgX2 receptors activated the corresponding rhesus receptors in cellular proliferation assays, Ca(2+)-mobilization assays, and GTP-gammaS-binding assays. Cortistatin-14 was selective for human and rhesus MrgX2 receptors over human and rhesus MrgX1 receptors. BAM22 and related peptides strongly activated human MrgX1 receptors, but weakly activated rhesus MrgX1, human MrgX2, and rhesus MrgX2 receptors. These data suggest that the rhesus monkey may be a suitable animal model for exploring the physiological roles of the MrgX receptors.     

Neuronal nicotinic acetylcholine receptors as drug targets

Neuronal nicotinic acetylcholine receptors (nAChRs) are an important class of ion channels that have been associated with a number of neurological conditions. A great deal of research has been focused on attempting to understand the exact physiological role of these receptors. As drug targets, the nAChRs are quite complex, both in their structure (multiple receptor subtypes) and their physiological function. Initially, the difficulty encountered in identifying small-molecule modulators led to doubts about the validity of this class of receptors as drug targets. More recently, in vitro and in vivo data, homology modelling, and the identification of small-molecule agonists, have confirmed nAChRs as valid drug discovery targets. In fact, several compounds are now in clinical development for the treatment of pain, smoking cessation and cognitive disorders.     

Neuronal nicotinic acetylcholine receptors as drug targets

Neuronal nicotinic acetylcholine receptors (nAChRs) are an important class of ion channels that have been associated with a number of neurological conditions. A great deal of research has been focused on attempting to understand the exact physiological role of these receptors. As drug targets, the nAChRs are quite complex, both in their structure (multiple receptor subtypes) and their physiological function. Initially, the difficulty encountered in identifying small-molecule modulators led to doubts about the validity of this class of receptors as drug targets. More recently, in vitro and in vivo data, homology modelling, and the identification of small-molecule agonists, have confirmed nAChRs as valid drug discovery targets. In fact, several compounds are now in clinical development for the treatment of pain, smoking cessation and cognitive disorders.     

Evidence for epsilon-opioid receptor-mediated beta-endorphin-induced analgesia.

Among the opioid receptors, which have been pharmacologically classified as mu, delta, kappa and epsilon, the existence of the epsilon receptor has been controversial, and this receptor is generally not recognized as a member of the opioid peptide receptor family because it has not been precisely characterized. However, results from pharmacological, physiological and opioid receptor binding studies clearly indicate the presence of epsilon-opioid receptors, which are distinct from mu-, delta- or kappa-opioid receptors. This putative epsilon-opioid receptor is stimulated supraspinally by the endogenous opioid peptide beta-endorphin, which induces the release of Met-enkephalin, which, in turn, acts on spinal delta2-opioid receptors to produce antinociception. In this article, this beta-endorphin-sensitive epsilon-opioid receptor-mediated descending pain control system, which is distinct from that activated by the mu-opioid receptor agonist morphine, is described and the physiological role of the beta-endorphin-mediated system in pain control activated by cold-water swimming and intraplantar injection of formalin is discussed.     

Adenosine and ATP receptors

Adenosine and ATP, via P1 and P2 receptors respectively, can modulate pain transmission under physiological, inflammatory, and neuropathic pain conditions. Such influences reflect peripheral and central actions and effects on neurons as well as other cell types. In general, adenosine A1 receptors produce inhibitory effects on pain in a number of preclinical models and are a focus of attention. In humans, i.v. infusions of adenosine reduce some aspects of neuropathic pain and can reduce postoperative pain. For P2X receptors, there is a significant body of information indicating that inhibition of P2X3 receptors may be useful for relieving inflammatory and neuropathic pain. More recently, data have begun to emerge implicating P2X4, P2X7 and P2Y receptors in aspects of pain transmission. Both P1 and P2 receptors may represent novel targets for pain relief.     

Therapeutic Potential of Metabotropic Glutamate Receptor Modulators

Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is a major player in complex brain functions. Glutamatergic transmission is primarily mediated by ionotropic glutamate receptors, which include NMDA, AMPA and kainate receptors. However, glutamate exerts modulatory actions through a family of metabotropic G-protein-coupled glutamate receptors (mGluRs). Dysfunctions of glutamatergic neurotransmission have been implicated in the etiology of several diseases. Therefore, pharmacological modulation of ionotropic glutamate receptors has been widely investigated as a potential therapeutic strategy for the treatment of several disorders associated with glutamatergic dysfunction. However, blockade of ionotropic glutamate receptors might be accompanied by severe side effects due to their vital role in many important physiological functions. A different strategy aimed at pharmacologically interfering with mGluR function has recently gained interest. Many subtype selective agonists and antagonists have been identified and widely used in preclinical studies as an attempt to elucidate the role of specific mGluRs subtypes in glutamatergic transmission. These studies have allowed linkage between specific subtypes and various physiological functions and more importantly to pathological states. This article reviews the currently available knowledge regarding the therapeutic potential of targeting mGluRs in the treatment of several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson’s disease, Alzheimer’s disease and pain.     

Glutamate-based therapeutic approaches: NR2B receptor antagonists

Over the past decade, there have been major advances in our understanding of the role of glutamate and N-methyl-d-aspartate (NMDA) receptors in several disorders of the central nervous system, including stroke, Parkinson's disease, Huntington's disease and chronic/neuropathic pain. In particular, NR2B subunit-containing NMDA receptors have been the focus of intense study from both a physiological and a pharmacological perspective, with several pharmaceutical companies developing NR2B subtype-selective antagonists for several glutamate-mediated diseases. Recent studies have shown the importance of NR2B subunits for NMDA receptor localization and endocytosis, and have suggested a role for NR2B-containing NMDA receptors in the underlying pathophysiology of neurodegenerative disorders such as Alzheimer's and Huntington's diseases. Anatomical, biochemical and pharmacological studies over the past five years have greatly added to our understanding of the role of NR2B subunit-containing NMDA receptors in chronic and neuropathic pain states, and have shown that NR2B-mediated analgesic effects might be supra- rather than intra-spinally mediated, and that phosphorylation of the NR2B subunit could be responsible for the initiation and maintenance of the central sensitization seen in neuropathic pain states. These data will hopefully provide the impetus for development of novel compounds that use multiple approaches to modulate the activity of NR2B subunit-containing NMDA receptors, thus bringing to fruition the promise of therapeutic efficacy utilizing this approach.     

Evidence for -opioid receptor-mediated β-endorphin-induced analgesia

Among the opioid receptors, which have been pharmacologically classified as μ, δ, κ and , the existence of the receptor has been controversial, and this receptor is generally not recognized as a member of the opioid peptide receptor family because it has not been precisely characterized. However, results from pharmacological, physiological and opioid receptor binding studies clearly indicate the presence of -opioid receptors, which are distinct from μ-, δ- or κ-opioid receptors. This putative -opioid receptor is stimulated supraspinally by the endogenous opioid peptide β-endorphin, which induces the release of Met-enkephalin, which, in turn, acts on spinal δ2-opioid receptors to produce antinociception. In this article, this β-endorphin-sensitive -opioid receptor-mediated descending pain control system, which is distinct from that activated by the μ-opioid receptor agonist morphine, is described and the physiological role of the β-endorphin-mediated system in pain control activated by cold-water swimming and intraplantar injection of formalin is discussed.     

Tegaserod: a serotonin 5-HT4 receptor agonist for treatment of constipation-predominant irritable bowel syndrome

Activation of serotonin 5-HT(4) receptors has been proposed as treatment for irritable bowel syndrome, a common, complex and distressing gastrointestinal disorder. Abnormal intestinal motility and sensitivity in irritable bowel syndrome patients can result in diarrhea, constipation, abdominal pain, bloating, headache and fatigue; these and other symptoms can lead to exacerbation of psychological stress, which may in turn induce further physiological abnormalities and patient discomfort. The serotonin agonist tegaserod binds with high affinity to 5-HT(4) receptors and has demonstrated potent pharmacological effects on the mid- and distal gut. Tegaserod has been safely employed in clinical trials where it has demonstrated efficacy in normalizing intestinal function, thereby improving irritable bowel syndrome symptoms.     

Targeting the cholinergic system as a therapeutic strategy for the treatment of pain

Acetylcholine mediates its effects through both the nicotinic acetylcholine receptors (ligand-gated ion channels) and the G protein-coupled muscarinic receptors. It plays pivotal roles in a diverse array of physiological processes and its activity is controlled through enzymatic degradation by acetylcholinesterase. The effects of receptor agonists and enzyme inhibitors, collectively termed cholinomimetics, in antinociception/analgesia are well established. These compounds successfully inhibit pain signaling in both humans and animals and are efficacious in a number of different preclinical and clinical pain models, suggesting a broad therapeutic potential. In this review we examine and discuss the evidence for the therapeutic exploitation of the cholinergic system as an approach to treat pain.