G蛋白偶联受体二聚化研究进展

G蛋白偶联受体(GPCR s)是最大的细胞膜受体家族,具有七螺旋跨膜肽段结构。近年来,越来越多的研究认为这些受体以二聚体的形式参与调节生理活动,对信号识别及转导有重要作用。随着生物技术及分子生物学的发展,GPCRs二聚体研究已取得了很大的进展。该文就这些方面及同源、异源二聚体对受体结合及信号转导的重要作用作一简述。     

G蛋白偶联受体119激动剂的研究进展

G蛋白偶联受体119 (GPR119)是治疗2型糖尿病有希望的靶点,它既可以直接促进胰岛素的分泌,也能够通过刺激葡萄糖依赖性GIP/CLP-1的释放间接增加胰岛素的分泌,而不引起低血糖。小分子GPR119激动剂具有显著的作用优势,使其成为开发2型糖尿病药物的研究热点之一。本文对近五年基于GPR119靶点的抗糖尿病活性小分子进行综述。     

针对G蛋白偶联受体的药物筛选新方法

G蛋白偶联受体（GPCR）为具有7个跨膜螺旋的蛋白质受体,是人体内最大的蛋白质家族,其为极重要的药物靶点。本文针对GPCR的固有激活和变构效应的药物筛选模型开发新进展和高内涵药物筛选新技术进行综述。     

细胞核G蛋白偶联受体研究进展

传统观念认为,G蛋白偶联受体通过自身在细胞表面的激活启动信号转导,从而介导细胞响应外界刺激.近年来研究发现了细胞核G蛋白偶联受体(nGPCR)的存在,有别于细胞质膜G蛋白偶联受体(mGPCR),细胞核G蛋白偶联受体具有独特的来源、功能、信号途径和作用模式.本文总结了目前对于细胞核G蛋白偶联受体的研究成果,以期为靶向G蛋...     

G蛋白偶联受体固有活性研究进展与新药开发

G蛋白偶联受体(G-prote in-coup led receptor,GPCR)是与G蛋白有信号连接的一大类受体家族,是人体内最大的膜受体蛋白家族,是一类具有7个跨膜螺旋的跨膜蛋白受体。GPCR的结构特征和在信号传导中的重要作用决定了其可以作为很好的药物靶标。目前世界药物市场上有三分之一的小分子药物是GPCR的激活剂(agon ist)或拮抗剂(antagon ist)。以其为靶点的药物在医药产业中占据显著地位。在当今前50种最畅销的上市药物中,20%属于G蛋白受体相关药物。近来的研究发现,大多数G蛋白偶联受体具有一个很重要的特性,就是具有固有活性(Constitutive ac-tivity),即无激动剂条件受体自发的维持激活并维持下游信号传导通路的活性。固有活性涉及受体、G蛋白及下游信号通路之间的关系。该文就G蛋白偶联受体固有活性概念、研究进展、反相激动剂与固有活性研究、固有活性与新药开发4个方面,进行以下论述。     

G蛋白偶联受体激酶和arrestins在受体调节中的作用

Ｇ 蛋白偶联受体（ Ｇｐｒｏｔｅｉｎ ｃｏｕｐｌｅｄ ｒｅｃｅｐｔｏｒ ， Ｇ Ｐ Ｃ Ｒｓ）是一大家族，介导许多激素的信号转导。在激动剂的持续作用下， Ｇ Ｐ Ｃ Ｒｓ 可发生对激动剂的敏感性下降，即受体减敏，现认为这一过程主要由 Ｇ 蛋白偶联受体激酶（ Ｇｐｒｏｔｅｉｎ ｃｏｕ ｐｌｅｄ ｒｅｃｅｐｔｏｒ ｋｉｎａｓｅｓ ， Ｇ Ｒ Ｋｓ） 和ａｒｒｅｓｔｉｎｓ 两大蛋白家族介导： Ｇ Ｒ Ｋｓ 先结合并磷酸化被激动剂占领的受体，然后ａｒｒｅｓｔｉｎｓ与磷酸化的受体结合，阻止受体与 Ｇ 蛋白发生作用，导致受体功能减退。近来发现， Ｇ Ｒ Ｋｓ 和ａｒｒｅｓｔｉｎｓ 还参与受体的内陷机制，而受体的复敏又与内陷密切相关     

G蛋白偶联受体119激动剂的研究进展

G蛋白偶联受体119(GPR119)是近年来发现的治疗糖尿病药物的重要靶标。该受体激动后,既能升高血浆中GLP-1水平又能增加胰岛素的分泌,近年来受到世界多个制药公司的重视,开发了多个GPR119激动剂,部分已经进入临床研究。本文对GPR119激动剂近年来的研究进展做一综述。     

烟碱受体变构调节和变构调节剂的研究进展

本文综述了烟碱受体变构调节的证据和变构调节剂的种类，指出变构调节发生在烟碱受体除识别位点以外的多个位点上，这些位点在受体与细胞膜交界的外侧、内侧、离子通道中和细胞膜上。膜片钳技术是重要研究手段之一，根据变构调节剂导致的烟碱受体性质的改变能确定它们的作用位点，这为进一步阐明烟碱受体的性质和明确一些药物的作用机制提供了依据。     

Allosteric modulation of G-protein coupled receptors.

The superfamily of G-protein coupled receptors (GPCRs) has more than 1000 members and is the largest family of proteins in the body. GPCRs mediate signalling of stimuli as diverse as light, ions, small molecules, peptides and proteins and are the targets for many pharmaceuticals. Most GPCR ligands are believed to activate (agonists) or inhibit (competitive antagonists) receptor signalling by binding the receptor at the same site as the endogenous agonist, the orthosteric site. In contrast, allosteric ligands modulate receptor function by binding to different regions in the receptor, allosteric sites. In recent years, combinatorial chemistry and high throughput screening have helped identify several allosteric GPCR modulators with novel structures, several of which already have become valuable pharmacological tools and may be candidates for clinical testing in the near future. This mini review outlines the current status and perspectives of allosteric modulation of GPCR function with emphasis on the pharmacology of endogenous and synthesised modulators, their receptor interactions and the therapeutic prospects of allosteric ligands compared to orthosteric ligands.     

Allosteric modulation of G-protein-coupled receptors

Allosteric modulation of G-protein-coupled receptors may provide an alternative approach for selective receptor interactions. The article is an overview of allosteric modulators enhancing or diminishing the effects of (endogenous) agonists or antagonists on a variety of G-protein-coupled receptors such as muscarinic, α-adrenergic, serotoninergic, dopaminergic, adenosine, metabotropic glutamate and Ca²⁺ receptors. Efficacious allosteric modulators have been published for the serotonin receptor (5-HT moduline; oleamide), the dopamine receptor (cyclic analogues of the tripeptide prolyl-leucyl-glycinamide), the metabotropic glutamate receptor (CPCCOET (mglu1); MPEP (mglu5)) and the Ca²⁺ receptor (NPS R-568; NPS 2143). Leads are available for the muscarinic (Ach) receptor (K5720) and the α_2A-adrenoceptor (agmatine). SCH-202676 and amiloride analogues are nonselective allosteric modifiers interacting with several different receptors. They may not be suitable as leads for future drugs but such compounds may be used for screening purposes.     

Allosteric binding sites on muscarinic receptors

The classical (acetylcholine) binding sites of all five subtypes of muscarinic receptors are known to be subject to allosteric regulation by a variety of small molecules. The hallmarks of such modulation in binding assays are that the allosteric ligands can alter both the affinities and the rates of association and dissociation of classical ligands. By the use of suitable combinations of allosteric ligands and appropriate models, it has been demonstrated that at least some of these ligands act via a single well-defined site. On the basis of protein-modification and mutational studies, it appears that these allosteric ligands bind to a part of the receptor that is extracellular to the classical binding site. The location of the allosteric site is likely the reason that the few ligands that have been found to increase the affinity of classical antagonists also cause a dramatic slowing of the kinetics of these classical ligands; the slowing can be so profound as to appear to reverse the increases in affinity. Fortunately, the effects of allosteric ligands on the kinetics of acetylcholine itself are not so problematic. Recent studies have described allosteric ligands that are capable of enhancing the affinity of acetylcholine in binding and response assays. Ligands of this class may prove to have quite useful applications, for example in restoring function lost due to depletion of acetylcholine. Drug Dev. Res. 40:193–204, 1997. © 1997 Wiley-Liss, Inc.     

G-protein coupled receptors regulating cough

Cough is a protective mechanism but can occur excessively in disease. Cough can be modulated by a range of GPCRs which can be either inhibitory or excitatory. Prostaglandin E2 and bradykinin can activate airway sensory nerves via EP3 and B2 receptors receptively and have both been shown to mediate their effects though TRPV1 and TRPA1 receptors. Activation of the β2-adrenoceptor and cannabinoid CB2 receptors can inhibit sensory nerves and prevent cough. It is currently thought that activation of the β2-adrenoceptor causes c-AMP dependent activation of PKA; however, recent research has suggested that the pathway involves PKG-mediated opening of the BKCa channel leading to hyperpolarization.     

Allosteric modulation of glycine receptors

Inhibitory (or strychnine sensitive) glycine receptors (GlyRs) are anion-selective transmitter-gated ion channels of the cys-loop superfamily, which includes among others also the inhibitory γ-aminobutyric acid receptors (GABA(A) receptors). While GABA mediates fast inhibitory neurotransmission throughout the CNS, the action of glycine as a fast inhibitory neurotransmitter is more restricted. This probably explains why GABA(A) receptors constitute a group of extremely successful drug targets in the treatment of a wide variety of CNS diseases, including anxiety, sleep disorders and epilepsy, while drugs specifically targeting GlyRs are virtually lacking. However, the spatially more restricted distribution of glycinergic inhibition may be advantageous in situations when a more localized enhancement of inhibition is sought. Inhibitory GlyRs are particularly relevant for the control of excitability in the mammalian spinal cord, brain stem and a few selected brain areas, such as the cerebellum and the retina. At these sites, GlyRs regulate important physiological functions, including respiratory rhythms, motor control, muscle tone and sensory as well as pain processing. In the hippocampus, RNA-edited high affinity extrasynaptic GlyRs may contribute to the pathology of temporal lobe epilepsy. Although specific modulators have not yet been identified, GlyRs still possess sites for allosteric modulation by a number of structurally diverse molecules, including alcohols, neurosteroids, cannabinoids, tropeines, general anaesthetics, certain neurotransmitters and cations. This review summarizes the present knowledge about this modulation and the molecular bases of the interactions involved.     

Target validation of G-protein coupled receptors

G-protein coupled receptors (GPCRs) represent possibly the most important target class of proteins for drug discovery. Over 30% of clinically marketed drugs are active at this receptor family. These drugs exhibit their activity at <10% of all known GPCRs. A major challenge for the pharmaceutical industry is to associate the many novel GPCRs with disease to identify the drugs of the future. This process consists of a collection of experimental paradigms that together can be loosely labelled 'target validation'.     

Co-ordinated covalent modification of G-protein coupled receptors

The G-protein coupled receptor (GPCR) gene family represents one of the largest families in the mammalian genome. The flexibility of signalling and widespread tissue distribution of these receptors has allowed GPCRs to be employed in the physiological regulation of nearly all biological functions. This, coupled with the fact that it is possible to chemically produce highly specific ligands to these receptors have made GPCRs attractive targets for pharmacological intervention in a wide variety of disease states. When targeting GPCRs in therapeutic drug design it is traditional, and eminently sensible, to focus on ligands that will provide agonism, antagonism or allosteric modulation. However, as more is understood of the mechanisms that regulate GPCRs, and in particular the dynamic covalent modifications that might endow tissue specific functions, then these regulatory processes may provide alternative targets for GPCR drug discovery. In this review we consider three of the covalent modifications which are considered to regulate the function of GPCRs namely; receptor phosphorylation, palmitoylation and ubiquitination. In particular, we will describe the mechanisms of modification, the functional consequences and the relationship between these three covalent modification events.     

Allosteric modulation of nicotinic acetylcholine receptors

Allosteric modulation refers to the concept that proteins could exist in multiple conformational states and that binding of allosteric ligands alters the energy barriers or "isomerization coefficients" between various states. In the context of ligand gated ion channels such as nicotinic acetylcholine receptors (nAChRs), it implies that endogenous ligand acetylcholine binds at the orthosteric site, and that molecules that bind elsewhere on the nAChR subunit(s) acts via allosteric interactions. For example, studies with the homomeric alpha7 nAChRs indicate that such ligand interactions can be well described by an allosteric model, and that positive allosteric effectors can affect energy transitions by (i) predominantly affecting the peak current response (Type I profile) or, (ii) both peak current responses and time course of agonist-evoked response (Type II profile). The recent discovery of chemically heterogeneous group of molecules capable of differentially modifying nAChR properties without interacting at the ligand binding site illustrates the adequacy of the allosteric model to predict functional consequences. In this review, we outline general principles of the allosteric concept and summarize the profiles of novel compounds that are emerging as allosteric modulators at the alpha7 and alpha4beta2 nAChR subtypes.