Research progress on role of free fatty acid receptors in nervous system diseases / 中国生物制品学杂志

@#Free fatty acid receptors(FFARs)are a series of orphan G protein-coupled receptors(GPCRs)activated by free fatty acids(FFAs)and their derivatives. As transmembrane receptors,GPCRs are involved in the occurrence and development of many diseases and provide a wide range of therapeutic targets for these diseases. FFARs combined with FFAs are mainly involved in the secretion of endocrine hormones such as insulin,adipocyte differentiation,inflammatory response,autoimmune response and other processes,which was a potential therapeutic target for energy metabolism disorders and immune diseases. However,recent studies have shown that FFAs and its receptor FFARs are widely involved in neuroinflammation and neuroimmunity directly or through the brain-intestinal axis,and are expected to be a therapeutic target for multiple sclerosis,Alzheimer′s disease(AD),Parkinson′s disease(PD),depression and other diseases. This paper reviews the research progress of the role of FFARs in nervous system diseases.

Research progress on receptor activity-modifying proteins and their application prospects in disease prevention / 中国生物制品学杂志

@#Receptor activity-modifying proteins(RAMPs) are type I transmembrane proteins,which are activity-modifying proteins of a variety of G-protein-coupled receptors(GPCRs).RAMPs are related to physiological and pathological phenomena such as neurological diseases,cardiovascular diseases,renal function,skeletal development and obesity,and of great significance for disease prevention,which are potential targets for the treatment of various diseases and also closely related to the prognosis of diseases.At present,there are few studies on proteins that may regulate the expression of RAMPs.This paper focuses on the sterol regulatory element-binding factor-2(SREBF-2) that may regulate the transcription and expression of RAMP3, and reviews the research progress of RAMPs in biology,pathology and pharmacology,providing a reference for the further research on RAMPs and the prevention and detection of related diseases.

Peptide Drugs Targeting G Protein-coupled Receptors / 中国生物化学与分子生物学报

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in mammals that contain seven transmembrane helices. The human genome encodes about 800 different types of GPCRs, which are widely involved in the pathological processes underlying different diseases, e.g. metabolic diseases and tumors, rendering them popular therapeutic targets. Peptides are organic substances consisted of two to dozens of amino acids linked by peptide bonds. They are bioactive substances involved in various cellular activities. To date, over 7 000 natural peptides have been identified as hormones, neurotransmitters, growth factors, ion channel ligands and antibiotics. Peptide drugs are valued for being selective and efficacious, and at the same time relatively safe and with low costs of production. In recent years, based on the increased understanding of GPCR structures, the development of GPCR-targeting peptide drugs has made great progress. Up to now, there have been nearly 50 peptide drugs targeting GPCRs approved by FDA for the treatment of metabolic diseases, nervous system diseases, cancer or other diseases. The research and development of peptide drugs have gone through three stages: development based on human peptides, on natural peptides and by modern biotechnology. At present, most of the marketed GPCR-targeting peptide drugs are derivatives of human natural peptides. In this review, we sum up the recent marketed GPCR-targeting peptide drugs, and also summarize the current strategies and further directions of peptide drug development.

New effect of G-protein coupled receptors on blood pressure regulation / 中国中药杂志

Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure, which may be accompanied by functional or organic damage of heart, brain, kidney and other organs. The pathogenesis and development of hypertension are affected by genetic, environmental, epigenetic, intestinal microbiota and other factors. They are the result of multiple factors that promote the change of blood pressure level and vascular resistance. G protein coupled receptors(GPCRs) are the largest and most diverse superfamily of transmembrane receptors that transmit signals across cell membranes and mediate a large number of cellular responses required by human physiology. A variety of GPCRs are involved in the control of blood pressure and the maintenance of normal function of cardiovascular system. Hypertension contributes to the damages of heart, brain, kidney, intestine and other organs. Many GPCRs are expressed in various organs to regulate blood pressure. Although many GPCRs have been used as therapeutic targets for hypertension, their efficacy has not been fully studied. The purpose of this paper is to elucidate the role of GPCRs in blood pressure regulation and its distribution in target organs. The relationship between GPCRs related to intestinal microorganisms and blood pressure is emphasized. It is proposed that traditional Chinese medicine may be a new way to treat hypertension by regulating the related GPCRs via intestinal microbial metabolites.

The current status of anti-GPCR drugs against different cancers / 药物分析学报

G protein coupled receptors (GPCRs) have emerged as the most potential target for a number of drug discovery programs ranging from control of blood pressure, diabetes, cure for genetic diseases to treatment of cancer. A panel of different ligands including hormones, peptides, ions and small molecules is responsible for activation of these receptors. Molecular genetics has identified key GPCRs, whose mutations or altered expressions are linked with tumorgenicity. In this review, we discussed recent advances regarding the involvement of GPCRs in the development of cancers and approaches to manipulating the mechanism behind GPCRs involved tumor growth and metastasis to treat different types of human cancer. This review provides an insight into the current scenario of GPCR-targeted therapy, progress to date and the challenges in the development of anticancer drugs.

G protein coupled receptors signaling pathways implicate in inflammatory and immune response of rheumatoid arthritis / 中国药理学与毒理学杂志

G protein coupled receptors (GPCRs) are transmembrane receptor proteins, which allow signals to transfer across membrane. GPCRs include a large number of receptors, different receptors mediated different signaling pathways of GPCRs- adenylyl cyclase (AC)- cyclic adenosine 3' ,5'-monophosphate (cAMP), including β2 adrenergic receptors (β2- ARs)- AC- cAMP signaling pathways, E-prostanoid2/4 (EP2/4)-AC-cAMP signaling pathways. Regulatory proteins, such as G protein coupled receptor kinases (GRKs) and β-arrestins, play important modulatory roles in GPCRs signaling pathway. GPCRs signaling pathway and regulatory proteins implicate the pathogenesis process of inflammatory and immune response. Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis and accompanied with inflammatory and abnormal immune response. This article review the advances on GPCRs signaling pathway implicating in the inflammatory and immune response of RA.

Progress in modulation of T-type calcium channels by ;G protein-coupled receptors / 中国药理学通报

T-type calcium channels are expressed in various tis-sues and play key roles in physiology and pathophysiology,inclu-ding neuronal firing,hormone secretion,pain,and cancer,etc. Hence,it is critical to understand the molecular mechanisms un-derlying the regulation of T-type channels.Substantial literature suggests many G protein-coupled receptors (GPCRs)and related second messengers can modulate T-type channel in some extent. Here,this review focuses on the modulation of T-type calcium channels by GPCRs and related second messengers.

Clinical Research - Past, Present & Future.

Clinical pharmacology/research has a very interesting history. It started in the 40's of the 20th century through the pioneering work of Harry Gold at Cornell University, New York. Clinical research is an integral part of drug development. Drug development can be hastened by a number of new techniques with reduction in cost. In addition reverse pharmacology approaches for drug discovery have come to occupy a special place. 85% of the neutral antagonists act as inverse agonists. Inverse agonists have a distinct effect on receptor regulation as opposed to neutral antagonists. Orphan receptors constitute about 50% of the GPCRs. It is estimated that now there are nearly 175 orphan receptors after 125 having been deorphanised. Targeting these orphan receptors can lead to about the same number of ligands and antagonists thereof. Polymorphism of cytochrome P450 provides the basis for the use of predictive pharmacogenomics to yield drug therapies that are more efficient and safer. It is estimated that such personalized P450 gene-based treatment would be relevant for 10- 20% of all drug therapy.

Visualization of serotonin 1A receptor trafficking in neuron-like PC12 cells / 基础医学与临床

Objective To explore the mechanisms of trafficking and signaling of serotonin 1A receptor(5-HT_(1A))and its spatiotemporal distribution in living cells.Methods The mouse 5-HT_(1A) gene amplified by RT-PCR was recombined into pEGFP-N1 vector and the EGFP coding sequence was located in-frame at the C-terminal end of the 5-HT_(1A) receptor.The 5-HT_(1A)-EGFP was transfected into neuron-like PC12 cells as well as HEK293.The transfected cells were visualized using confocal microscopy,the mobility of 5-HT_(1A)-EGFP was monitored by live measurements and fluorescence recovery after photobleaching.Results The 5-HT_(1A) gene was identitical with the published gene sequence NM_008308.4 and a 5-HT_(1A)-EGFP fusion construct was created.After stable transfection of the plasimd into a PC12 cell line and analysis with a confocal laser scanning microscopy,the EGFP-tagged 5-HT_(1A) was predominantly associated with the plasma membrane,but some intracellular vesicles in the perinuclear region also contained the fusion protein.The predominant localization of 5-HT_(1A)-EGFP at the plasma membrane was confirmed in transiently transfected HEK293 cells.Bleached fluorescence was partialy recovered in 100 seconds,indicating that the 5-HT_(1A)-EGFP was mobiled on the membrane.Conclusion Spatiotemporal distribution and mobility of 5-HT_(1A) tagged with EGFP can be monitored in the 5-HT_(1A)-EGFP stable PC12 cell line,which could be an excellent neuron-like experimental cell model for research of 5-HT_(1A) trafficking and signaling.

Analysis of glucose-dependent insulinotropic peptide receptor (GIPR) and luteinizing hormone receptor (LHCGR) expression in human adrenocortical hyperplasia / Análise da expressão dos receptores do peptídeo insulinotrópico dependente de glicose (GIPR) e do hormônio luteinizante (LHCGR) nas hiperplasias adrenocorticais humanas

OBJECTIVE: To analyze the aberrant expression of the GIPR and LHCGR in different forms of adrenocortical hyperplasia: ACTH-independent macronodular adrenal hyperplasia (AIMAH), primary pigmented nodular adrenocortical disease (PPNAD) and diffuse adrenal hyperplasia secondary to Cushing's disease (DAHCD). METHODS: We quantified GIPR and LHCGR expressions using real time PCR in 20 patients with adrenocortical hyperplasia (seven with AIMAH, five with PPNAD, and eight with DAHCD). Normal adrenals tissues were used as control and the relative expression was compared with β-actin. RESULTS: GIPR and LHCGR expressions were demonstrated in all tissues studied. Median GIPR and LHCGR mRNA levels were 1.6; 0.4; 0.5 and 1.3; 0.9; 1.0 in adrenocortical tissues from AIMAH, PPNAD and DAHCD respectively. There were no differences between GIPR and LHCGR expressions in all tissues studied. CONCLUSIONS: GIPR and LHCGR overexpression were not identified in the studied cases, thus suggesting that this molecular mechanism is not involved in adrenocortical hyperplasia in our patients.

OBJETIVO: Analisar a expressão aberrante do GIPR e do LHCGR em diferentes formas de hiperplasias adrenocorticais: hiperplasia adrenal macronodular independente de ACTH (AIMAH), doença adrenocortical nodular pigmentada primária (PPNAD) e hiperplasia adrenal difusa secundária à doença de Cushing (DAHCD). MÉTODOS: Quantificou-se por PCR em tempo real a expressão desses receptores em 20 pacientes: sete com AIMAH, cinco com PPNAD e oito com DAHCD. Adrenais normais foram utilizadas como controle e a expressão relativa desses receptores foi comparada à expressão da β-actina. RESULTADOS: A expressão desses receptores foi demonstrada em todos os tecidos estudados. A mediana da expressão do GIPR e do LHCGR foi de 1,6; 0,4; 0,5 e de 1,3; 0,9; 1,0 nos tecidos dos pacientes com AIMAH, PPNAD e DAHCD, respectivamente. Não houve diferença significativa na expressão desses receptores nos tecidos estudados. CONCLUSÕES: Hiperexpressão do GIPR e do LHCGR não foi observada, sugerindo que esse mecanismo não está envolvido na patogênese molecular da hiperplasia adrenal nesses pacientes.

The Odorant Signaling Pathway

Through the sense of smell mammals can obtain information about food, danger, sexual partners and predators. Two main different types of signals can be recognized by the olfactory system: volatile odorants, which are detected by the olfactory sensory neurons of the nose; and pheromones, which are detected by the vomeronasal neurons of the accessory olfactory system, or vomeronasal organ. These sensory neurons express respectively hundreds of odorant and pheromone receptors, which belong to the superfamily of G protein-coupled receptors. We review the general organization of the main and accessory olfactory systems, the structures of the receptor families in each of these organs and their signaling pathways.

Pharmacological development of G protein-coupled receptors allosteric modulation / 中国药理学通报

G protein-coupled receptors(GPCRs)mediate cell signaling transduction of most hormones and neurological transmitters and behave as the key targets for drug research and development.Recently,the evidence of allosteric modulation of GPCRs has been revealed.Allosteric modulators have the ability to selectively tune responses only in tissues in which the endogenous agonist exerts its physiological effects,and have the potential for greater receptor subtype selectivity.The GPCRs allosteric modulators have been found and some of them have been in clinical use.Under the strategy of allosterism on structure activity relationship and target directed screening,more and more GPCRs allosteric modulators will be developed in the future.

Allosteric regulation of G-protein coupled receptors / 中国药理学通报

Despite the important properties of GPCRs as drug targets,improving the subtype selectivity and efficiency of new drugs targeting at GPCRs is a predominant challenge.The study of GPCRs allosterism shows there exist great complexity and diversity in allosterism and allosteric sites,and it also provides a new opportunity for exploring new drugs with subtype selectivity and efficiency.This review summaries the development of GPCRs allosterism in recent years and shows GPCRs allosterism and its biological significance.

Dimerization of G protein-coupled receptors and its possible role in signaling trasduction / 中国药理学通报

G-protein coupled receptors(GPCRs)belong to the biggest subfamily of transmembran receptors.Recently,more and more research has been suggested that the dimerization of GPCRs may regulate the physiological and pharmacological activity.With the development of biochemistry technology and molecular biology,a great progress has been achieved in the field of the dimerization of GPCRs.This article will generally demonstrate that the vital roles of the homodimerization and heterdimerization.

Orphan G protein-coupled receptors and their significance as novel drug targets / 中国药理学通报

G protein-coupled receptors(GPCRs) are the largest and most diverse group of trans-membrane proteins involved in signal transduction. They have been playing key roles in drug discover-y. Increasing orphan GPCRs (oGPCRs) whose endogenous ligands and functions are still to be identified have been discovered in recent years. It is obvious that oGPCRs might be the most important targets for innovating drugs.