游离脂肪酸受体的结构、分布及功能

游离脂肪酸的生理功能及其与某些疾病的相关性长期以来受到人们的关注。由于特异性膜受体一直未被发现．关于其分子机制的认识无法深入。最近的研究表明,长链脂肪酸是孤儿型G蛋白偶联受体GPR40的配基．而短链脂肪酸则是孤儿型G蛋白偶联受体GPR4l和GPR43的配基。体外实验显示,长链脂肪酸通过GPR40增强胰岛B细胞的分泌功能;短链脂肪酸经GPR41刺激脂肪细胞中瘦蛋白(1eptin)的产生。GPR43在白细胞活化过程中发挥一定的作用。作为潜在的药物作用靶点,游离脂肪酸特异性受体为寻找治疗代谢性疾病的新手段指明了的方向。     

G蛋白偶联受体40研究进展

G蛋白偶联受体40(G protein-coupled receptor 40, GPR40)是一种具有7个跨膜α螺旋结构的G蛋白偶联受体, 主要分布于胰腺细胞和神经系统细胞。它能与机体内游离的中长链脂肪酸结合, 激活细胞内信号通路, 从而调节其生理功能。在胰岛细胞中, GPR40可被游离脂肪酸激活, 促使细胞内钙离子浓度升高, 进而促进胰岛素释放。根据这一机理, 以GPR40为靶点的激动剂类药物相继被开发, 用于糖尿病治疗。GPR40也参与神经发生过程, 但到目前为止其相关机制尚不清楚。文章从基因结构、表达调控、蛋白配体及应用、生理功能等方面详细介绍了GPR40的研究现状, 总结了目前研究中所遇到的问题, 并对未来的研究热点进行展望。     

生长抑素受体的生理功能及动力学特征

生长抑素受体家族(somatostatin receptors,SSTRs)是一类介导生长抑素及其类似物,具有多种生物学效应的G蛋白偶联受体家族,其生理功能和作用机制长期以来倍受关注.研究表明,这些细胞膜上存在的特定膜受体包括SSTR1、SSTR2、SSTR3、SSTR4以及SSTR5,可以通过cAMP、PTP和MAPK信号通路,在调控GH分泌、诱导细胞凋亡、抑制肿瘤细胞增生、抑制胰岛素作用和抑制细胞生长等生物学过程发挥重要的作用,同时表现出与其它G蛋白偶联受体性质相似的动力学特征.本文将SSTRs的结构、分布和生理功能、配体选择性、下游信号通路,以及该受体家族的动力学特征最新研究进展作一综述.     

mGluR 1／5介导的下游信号通路

代谢型谷氨酸受体l／5（mGluR1／5）是G蛋白偶联受体家族C的重要成员之一,该受体及其介导的下游信号在调节神经系统的正常生理功能起着非常重要作用,并与相关神经系统退行性疾病密切相关。文章介绍了mGluR1／5所介导的信号通路、信号通路调控的分子机制以及其他GPCR受体的相互作用对信号共同调节的分子机制等方面最新研究进展。     

一个潜在的糖尿病新靶标——GPR40

G蛋白偶联受体40(GPR40)是典型的七次跨膜受体,在游离脂肪酸的刺激下,它能起到放大葡萄糖刺激的胰岛素分泌效应,是一种潜在的治疗糖尿病药物的靶标。另外,GPR40还被认为和一些神经类疾病以及某些癌症有关。本文着重叙述了游离脂肪酸经由GPR40放大葡萄糖刺激的胰岛素分泌机制,同时也介绍了GPR40的其他一些生理功能。     

G蛋白偶联受体的结构与功能

G蛋白偶联受体(Gprotein-coupled receptor,GPCR)是具有7个跨膜螺旋的蛋白质受体,根据其序列的相似性以及与配基的结合情况,共分为5个亚家族,是人体内最大的蛋白质家族,也是重要的药物靶标。二聚体或寡聚体的形成,以及G蛋白偶联受体多元素参与的信号网络传递模式的研究,打破了传统的配基→G蛋白偶联受体→G蛋白→效应器的这种单一的线性信号传递模式,它的结构与功能的研究对于新药的开发、研制以及推动医药领域的发展起着举足轻重的作用。     

与癌症相关的G 蛋白偶联受体及通路的研究进展

G蛋白偶联受体(G protein-coupled receptors,GPCRs)是一类重要的细胞膜表面跨膜蛋白受体超家族,具有7个跨膜螺旋结构。GPCRs的细胞内信号由G蛋白介导,可将激素、神经递质、药物、趋化因子等多种物理和化学的细胞外刺激穿过细胞膜转导到细胞内不同的效应分子,激活相应的信号级联系统进而影响恶性肿瘤的生长迁移过程。虽然目前药物市场上有很多治疗癌症的小分子药物属于G蛋白受体相关药物,但所作用的靶点集中于少数特定G蛋白偶联受体。因此,新的具有成药性的G蛋白偶联受体的开发具有很大的研究价值和市场潜力。本文主要以在癌症发生、发展中起重要作用的溶血磷脂酸(LPA),G蛋白偶联受体30(GPR30)、内皮素A受体(ETAR)等不同G蛋白偶联受体为分类依据,综述其与相关的信号通路在癌症进程中的作用,并对相应的小分子药物的临床应用和研究进展进行展望。     

质子感知受体与肿瘤发生和肿瘤转移之间的关系

G蛋白偶联受体家族卵巢癌G蛋白偶联受体1（ovarian cancer G protein-coupled receptor 1, OGR1）亚家族的OGR1、T细胞死亡偶联基因8（T－cell death associated gene 8, TDAG8）、G 蛋白偶联受体4（G protein－coupled receptor 4, GPR4）及诱导细胞停滞于G2/M期的G蛋白偶联受体G2A（from G2 accumulation）4 种受体是最新发现的一类质子感知受体.除了质子,体内又有它们各自特定的脂质分 子配体活化这些受体来调节细胞机能.该类受体广泛分布于人的各种正常组织和肿瘤 组织细胞中,在肿瘤的发生与转移、细胞骨架重组等生理病理过程中发挥双重作用. 正常表达时它们有一定的抑制肿瘤作用,但这些受体的异常表达或过表达使某些组织 和细胞恶性转化,导致肿瘤的发生.本文综述了在肿瘤组织的酸性微环境中,细胞表 达的质子（pH）感知受体对肿瘤发生与肿瘤转移的调节作用及其相关的信号通路.     

G蛋白偶联受体相关分选蛋白功能特征与相关疾病研究进展

G蛋白偶联受体(G protein-coupled receptors, GPCRs)作为最大的一类膜蛋白受体家族,可被多种配体激活并发挥相应的信号转导功能,参与生物体内重要的生理过程。G蛋白偶联受体相关分选蛋白(G protein-coupled receptors associated sorting proteins, GASPs)则对内吞后的GPCRs分选过程发挥着重要的作用,并介导受体进入降解或再循环途径,进而调控细胞的信号转导等过程。研究发现GASPs的功能缺陷与多种疾病相关,包括神经系统疾病、肿瘤和耳聋等。本文重点介绍了G蛋白偶联受体相关分选蛋白的功能特征及其相关信号通路,描述了GASPs功能缺陷与疾病的关联性及家族蛋白与GPCRs的相互作用、GASPs分选途径的发现、参与的信号通路及对基因转录调控,以期为GASPs相关多种疾病的治疗提供新的思路和策略。     

β-arrestin的生物学研究进展

β-arrestin 1和2是一类介导受体脱敏的重要可溶性蛋白质,对绝大部分与受体偶联G蛋白介导的信号转导具有重要调节作用,在G蛋白偶联受体(G protein-coupled receptors, GPCRs)脱敏、内化、复敏、细胞增殖反应和基因转录中具有重要地位.对β-arrestin介导的复杂信号通路的研究将揭示它们的调节功能对人类健康的影响,有助于开发新一代影响GPCRs的药物.     

Role of free fatty acid receptors in the regulation of energy metabolism

Free fatty acids (FFAs) are energy-generating nutrients that act as signaling molecules in various cellular processes. Several orphan G protein-coupled receptors (GPCRs) that act as FFA receptors (FFARs) have been identified and play important physiological roles in various diseases. FFA ligands are obtained from food sources and metabolites produced during digestion and lipase degradation of triglyceride stores. FFARs can be grouped according to ligand profiles, depending on the length of carbon chains of the FFAs. Medium- and long-chain FFAs activate FFA1/GPR40 and FFA4/GPR120. Short-chain FFAs activate FFA2/GPR43 and FFA3/GPR41. However, only medium-chain FFAs, and not long-chain FFAs, activate GPR84 receptor. A number of pharmacological and physiological studies have shown that these receptors are expressed in various tissues and are primarily involved in energy metabolism. Because an impairment of these processes is a part of the pathology of obesity and type 2 diabetes, FFARs are considered as key therapeutic targets. Here, we reviewed recently published studies on the physiological functions of these receptors, primarily focusing on energy homeostasis.     

G protein-coupled receptors for free fatty acids

Free fatty acids (FFAs) are not only an important direct source of energy but they also play key roles in regulating a range of physiological responses. Although it was long assumed that such effects of FFAs must occur following cellular uptake, and potentially via their conversion to fatty acyl-CoAs, it is now apparent that FFAs also function directly as agonists at a number of G protein-coupled receptors (GPCRs). Tissue distribution studies and, subsequently, siRNA knock-down experiments have indicated key roles for these GPCRs in glucose homeostasis, adipogenesis, white cell recruitment and potentially in a range of other processes. Considerable interest is thus now centred on the generation of potent and selective small molecule ligands, both as tool compounds to further unravel the biology and physiological role of this group of GPCRs and as starting points for possible therapeutic intervention in a range of areas, particularly those associated with 'metabolic syndrome'.     

GPR120的研究进展

游离脂肪酸作为组织能量来源以及介导各种细胞进程的信号分子,其生理功能长期以来受到广泛关注。外周游离脂肪酸水平的升高与肥胖、脂代谢紊乱以及糖尿病紧密相关。GPR120作为一新的长链脂肪酸受体,参与调节体内一系列的代谢过程,如激素分泌、细胞增殖及脂质生成等。作为肥胖、糖尿病的潜在治疗靶标,值得更深入的研究。     

Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84

Free fatty acids (FFAs) play important physiological roles in many tissues as an energy source and as signaling molecules in various cellular processes. Elevated levels of circulating FFAs are associated with obesity, dyslipidemia, and diabetes. Here we show that GPR84, a previously orphan G protein-coupled receptor, functions as a receptor for medium-chain FFAs with carbon chain lengths of 9-14. Medium-chain FFAs elicit calcium mobilization, inhibit 3',5'-cyclic AMP production, and stimulate [35S]guanosine 5'-O-(3-thiotriphosphate) binding in a GPR84-dependent manner. The activation of GPR84 by medium-chain FFAs couples primarily to a pertussis toxin-sensitive G(i/o) pathway. In addition, we show that GPR84 is selectively expressed in leukocytes and markedly induced in monocytes/macrophages upon activation by lipopolysaccharide. Furthermore, we demonstrate that medium-chain FFAs amplify lipopolysaccharide-stimulated production of the proinflammatory cytokine interleukin-12 p40 through GPR84. Our results indicate a role for GPR84 in directly linking fatty acid metabolism to immunological regulation.     

A family of fatty acid binding receptors

The family of G protein-coupled receptors (GPCRs) serves as the target for almost a third of currently marketed drugs, and provides the predominant mechanism through which extracellular factors transmit signals to the cell. The discovery of GPCRs with no known ligand has initiated a frenzy of research, with the aim of elucidating the physiological ligands for these "orphan" receptors and revealing new drug targets. The GPR40 family of receptors, tandemly located on chromosome 19q13.1, exhibit 30-40% homology to one another and diverse tissue distribution, yet all are activated by fatty acids. Since agonists of GPR40 are medium to longchain fatty acids and those for GPR41 and 43 are short-chain fatty acids, the family clearly provides an intriguing example of how the ligand specificity, patterns of expression, and function of GPCRs can diverge through evolution. Here we summarize the identification, structure, and pharmacology of the receptors and speculate on the respective physiological roles that the GPR40 family members may play.     

Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1

Free fatty acids (FFAs) provide an important energy source and also act as signaling molecules. FFAs are known to exert a variety of physiological responses via their G protein-coupled receptors (GPCRs), such as the GPR40 family. Recently, we identified a novel FFA receptor, GPR120, that promotes secretion of glucagon-like peptide-1 (Hirasawa, A., Tsumaya, K., Awaji, T., Katsuma, S., Adachi, T., Yamada, M., Sugimoto, Y., Miyazaki, S., and Tsujimoto, G. (2005) Nat. Med. 11, 90-94). Here we showed that FFAs inhibit serum deprivation-induced apoptosis of murine enteroendocrine STC-1 cells, which express two types of GPCRs, GPR120 and GPR40, for unsaturated long chain FFA. We first found that linolenic acid potently activated ERK and Akt/protein kinase B (Akt) in STC-1 cells. ERK kinase inhibitors significantly reduced the anti-apoptotic effects of linolenic acid. Inhibitors for phosphatidylinositol 3-kinase (PI3K), a major target of which is Akt, significantly reduced the anti-apoptotic effects. Transfection of STC-1 cells with the dominant-negative form of Akt also inhibited the anti-apoptotic effect. These results suggested that the activation of ERK and PI3K-Akt pathways is required for FFA-induced anti-apoptotic effects on STC-1 cells. Transient transfection of STC-1 cells with GPR120 cDNA, but not GPR40 cDNA, enhanced inhibition of caspase-3 activation. RNA interference experiments showed that reduced expression of GPR120, but not GPR40, resulted in reduced ERK activation and reduced effects of FFAs on caspase-3 inhibition. Collectively, these results demonstrated that FFAs promote the activation of ERK and PI3K-Akt pathways mainly via GPR120, leading to the anti-apoptotic effect of STC-1 cells.     

游离脂肪酸受体蛋白研究进展

游离脂肪酸不仅是人和动物体的一种重要能量来源,也是一种重要的信号分子。最近研究表明,游离脂肪酸受体蛋白在维持机体内的葡萄糖稳衡、脂肪形成、白细胞功能等生理过程中都有重要的作用,对于调控人或动物的营养代谢及疾病发生具有重要生理意义。     

Structural basis for GPCR signaling by small polar versus large lipid metabolites—discovery of non-metabolite ligands

Key metabolites act through specific G protein-coupled receptors (GPCRs) as extracellular signals of fuel availability and metabolic stress. Here, we focus on the succinate receptor SUCNR1/GPR91 and the long chain fatty acid receptor FFAR1/GPR40, for which 3D structural information is available. Like other small polar acidic metabolites, succinate is excreted from the cell by transporter proteins to bind to an extracellular, solvent-exposed pocket in SUCNR1. Non-metabolite pharmacological tool compounds are currently being designed based on the structure of the SUCNR1 binding pocket. In FFAR1, differently signaling lipid mimetics bind in two distinct membrane-exposed sites corresponding to each of the lipid bilayer leaflets. Conceivably endogenous lipid ligands gain access to these sites by way of the membrane and probably occupy both sites under physiological circumstances. Design of polar agonists for a dynamic, solvent-exposed pocket in FFAR1 underlines the possibility of structure-based approaches for development of novel tool compounds even in lipid sensing metabolite GPCRs.     

Production and characterization of a monoclonal antibody against GPR40 (FFAR1; free fatty acid receptor 1)

GPR40 is G protein-coupled receptor whose endogenous ligands have recently been identified as free fatty acids (FFAs), and it has been implicated to play an important role in FFA-mediated enhancement of glucose-stimulated insulin release. We have developed a monoclonal antibody against the extracellular domain of GPR40. Specificity of the antibody was demonstrated by immunoprecipitation and cell surface staining using GPR40-transfected cells. GPR40 immunoreactivity was highly abundant in mouse pancreatic β-cells and splenocytes, THP-1 cells, and human peripheral blood mononuclear cells. The anti-GPR40 monoclonal antibody should prove valuable for further studying the function of this nutrient sensing receptor.     

The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse

Obesity is typically associated with elevated levels of free fatty acids (FFAs) and is linked to glucose intolerance and type 2 diabetes. FFAs exert divergent effects on insulin secretion from beta cells: acute exposure to FFAs stimulates insulin secretion, whereas chronic exposure impairs insulin secretion. The G protein-coupled receptor GPR40 is selectively expressed in beta cells and is activated by FFAs. We show here that GPR40 mediates both acute and chronic effects of FFAs on insulin secretion and that GPR40 signaling is linked to impaired glucose homeostasis. GPR40-deficient beta cells secrete less insulin in response to FFAs, and loss of GPR40 protects mice from obesity-induced hyperinsulinemia, hepatic steatosis, hypertriglyceridemia, increased hepatic glucose output, hyperglycemia, and glucose intolerance. Conversely, overexpression of GPR40 in beta cells of mice leads to impaired beta cell function, hypoinsulinemia, and diabetes. These results suggest that GPR40 plays an important role in the chain of events linking obesity and type 2 diabetes.