G protein-coupled receptor 37 (GPR37), also known as parkin associated endothelin-like (Pael) receptor, is an orphan G protein- coupled receptor, which suffers a defective parking ubiquitination in autosomal recessive...G protein-coupled receptor 37 (GPR37), also known as parkin associated endothelin-like (Pael) receptor, is an orphan G protein- coupled receptor, which suffers a defective parking ubiquitination in autosomal recessive Parkinson’s disease promoting its endoplasmic reticulum aggregation and stress, neurotoxicity and neuronal death (Takahashi and Imai, 2003). Interestingly, we have demonstrated previously that GPR37 heteromerizes with adenosine A2A receptor (A2AR) in the striatum (Morato et al., 2017;Sokolina et al., 2017).展开更多
We cloned the complete coding sequences of porcine Gpr3, Gpr6, and Gpr12 genes. Further, on the basis of their high levels of sequence similarity, these genes are identified as a subfamily of G protein-coupled recepto...We cloned the complete coding sequences of porcine Gpr3, Gpr6, and Gpr12 genes. Further, on the basis of their high levels of sequence similarity, these genes are identified as a subfamily of G protein-coupled receptors. These putative protein sequences also showed high sequence identity with other mammalian orthologs, including several highly conserved motifs. A wide expression of the Gpr3 gene in pigs was observed through tissue distribution analysis by reverse transcriptase-polymerase chain reaction （RT-PCR） and real-time PCR, specially in the brain, pituitary, fat, liver and oocyte, where its strong expression was observed. The Gpr3 gene was found to be located on chromosome 6 and a single exon coded for the entire open reading frame. Expression of porcine Gpr3 in HEK293 cells resulted in constitutive activation of adenylate cyclase （AC） similar in amplitude to that produced by fully stimulated Gs coupled receptors. Moreover, sphingosine 1-phosphate （S1P） could increase AC activation via the constitutively active Gpr3 receptor. When a Gpr3-green fluorescent protein （GFP） construct was expressed in HEK293 cells, GFP-labeled Gpr3 protein was shown to be localized in the plasmalemma and subcellular membranes. After S1P treatment, agonist-mediated internalization could be visualized by confocal microscopy. In short, our findings suggest the porcine Gpr3, Gpr6, and Gpr12 genes as a subfamily of G protein-coupled receptors, and porcine Gpr3 was a constitutively active G protein-coupled receptor. Constitutive activation of AG and agonist-mediated internalization of Gpr3 receptor could be modulated by the S1 P, suggesting that S1P might act as an activator for porcine Gpr3 receptor.展开更多
Adhesion G protein-coupled receptors(aGPCRs)are the second largest diverse group within the GPCR superfamily,which play critical roles in many physiological and patho-logical processes through cell-cell and cell-extra...Adhesion G protein-coupled receptors(aGPCRs)are the second largest diverse group within the GPCR superfamily,which play critical roles in many physiological and patho-logical processes through cell-cell and cell-extracellular matrix interactions.The adhesion GPCR Adgrg6,also known as GPR126,is one of the better-characterized aGPCRs.GPR126 was previously found to have critical developmental roles in Schwann cell maturation and its mediated myelination in the peripheral nervous system in both zebrafish and mammals.Current studies have extended our understanding of GPR126-mediated roles during develop-ment and in human diseases.In this review,we highlighted these recent advances in GPR126 in expression profile,molecular structure,ligand-receptor interactions,and associated physiological and pathological functions in development and diseases.展开更多
G protein-coupled receptor 91(GPR91)has garnered widespread attention as a prospective therapeutic target for metabolic diseases.However,no structural data for human GPR91(hGPR91);detailed molecular mechanism of actio...G protein-coupled receptor 91(GPR91)has garnered widespread attention as a prospective therapeutic target for metabolic diseases.However,no structural data for human GPR91(hGPR91);detailed molecular mechanism of action(MOA)of GPR91 have been reported,with reported compounds targeting GPR91 limited.In this study,hGPR91 structures were constructed through homology modeling.High-affinity agonist compound 31 and antagonist NF-58-EJ40 were selected for investigation.By molecular dynamics(MD)simulations,we have elucidated MOA of GPR91 agonists and antagonists for the first time.We identified the crucial role of the D174FASSG sequence,the L652.46SVSD2.50 sequence and the N642.45-W1474.50 in maintaining GPR91’s inactive state conformation.Agonist binding disrupted constraints mediated by the aforementioned sequence,which led to significant outward movements of transmembrane helixes(TMs);repositioning of intracellular loop2(ICL2);ICL3,thereby forming an expanded cavity for G proteins binding.Furthermore,the pivotal role of the dicarboxylic acid structure of agonists in initiating signal transduction was confirmed.In contrast,antagonist binding stabilized these conformational constraints,resulting in relatively minor movements of TMs that were insufficient to generate a binding cavity large enough to accommodate the G protein.Clarifying MOA of GPR91 agonists and antagonists is crucial for guiding the design of relevant drugs.展开更多
基金Fondo Europeo de Desarrollo Regional(FEDER)/Ministerio de Ciencia,Innovacion y Universidades–Agencia Estatal de Investigacion(SAF2017-87349-R)Instituto de Salud Carlos Ⅲ(ISCⅢ)(PIE14/00034)+3 种基金the Catalan government(2017 SGR 1604)Fundaciola Maratode TV3(Grant 20152031)Fonds Wetenschappelijk Onderzoek(FWO)(SBO-140028)to FC and Centro 2020(projects CENTRO-01-0145-FEDER-000008:BrainHealth 2020 and CENTRO-01-0246-FEDER-000010)Fundacao para a Ciencia e a Tecnologia(FCT)(projects PTDC/NEU-NMC/4154/2014 and POCI-01-0145-FEDER-031274) to RAC
文摘G protein-coupled receptor 37 (GPR37), also known as parkin associated endothelin-like (Pael) receptor, is an orphan G protein- coupled receptor, which suffers a defective parking ubiquitination in autosomal recessive Parkinson’s disease promoting its endoplasmic reticulum aggregation and stress, neurotoxicity and neuronal death (Takahashi and Imai, 2003). Interestingly, we have demonstrated previously that GPR37 heteromerizes with adenosine A2A receptor (A2AR) in the striatum (Morato et al., 2017;Sokolina et al., 2017).
基金Project supported by the National High-Tech R&D Program(863)of China(No.2006AA10Z136)a Grant-in-Aid for Innovative Training of Doctoral Students in Jiangsu Province of China(No.CXLX11-0701)
文摘We cloned the complete coding sequences of porcine Gpr3, Gpr6, and Gpr12 genes. Further, on the basis of their high levels of sequence similarity, these genes are identified as a subfamily of G protein-coupled receptors. These putative protein sequences also showed high sequence identity with other mammalian orthologs, including several highly conserved motifs. A wide expression of the Gpr3 gene in pigs was observed through tissue distribution analysis by reverse transcriptase-polymerase chain reaction （RT-PCR） and real-time PCR, specially in the brain, pituitary, fat, liver and oocyte, where its strong expression was observed. The Gpr3 gene was found to be located on chromosome 6 and a single exon coded for the entire open reading frame. Expression of porcine Gpr3 in HEK293 cells resulted in constitutive activation of adenylate cyclase （AC） similar in amplitude to that produced by fully stimulated Gs coupled receptors. Moreover, sphingosine 1-phosphate （S1P） could increase AC activation via the constitutively active Gpr3 receptor. When a Gpr3-green fluorescent protein （GFP） construct was expressed in HEK293 cells, GFP-labeled Gpr3 protein was shown to be localized in the plasmalemma and subcellular membranes. After S1P treatment, agonist-mediated internalization could be visualized by confocal microscopy. In short, our findings suggest the porcine Gpr3, Gpr6, and Gpr12 genes as a subfamily of G protein-coupled receptors, and porcine Gpr3 was a constitutively active G protein-coupled receptor. Constitutive activation of AG and agonist-mediated internalization of Gpr3 receptor could be modulated by the S1 P, suggesting that S1P might act as an activator for porcine Gpr3 receptor.
基金supported by the National Natural Science Foundation of China(No.32200778)the Natural Science Foundation of Jiangsu Province,China(No.BK20220494)+3 种基金Suzhou Medical and Health Technology Innovation Project(China)(No.SKY2022107)startup fund of Soochow University(China)(No.NH21500221,NH21500122)the Clinical Research Center of Neurological Disease in The Second Affiliated Hospital of Soochow University,China(No.ND2022A04 to Qifei Cong)the Nantong Municipal Health and Family Planning Commission(China)(No.QA2021017 to Xin Chu).
文摘Adhesion G protein-coupled receptors(aGPCRs)are the second largest diverse group within the GPCR superfamily,which play critical roles in many physiological and patho-logical processes through cell-cell and cell-extracellular matrix interactions.The adhesion GPCR Adgrg6,also known as GPR126,is one of the better-characterized aGPCRs.GPR126 was previously found to have critical developmental roles in Schwann cell maturation and its mediated myelination in the peripheral nervous system in both zebrafish and mammals.Current studies have extended our understanding of GPR126-mediated roles during develop-ment and in human diseases.In this review,we highlighted these recent advances in GPR126 in expression profile,molecular structure,ligand-receptor interactions,and associated physiological and pathological functions in development and diseases.
基金supported by the National Natural Science Foundation of China(Nos.82073765,82273853).
文摘G protein-coupled receptor 91(GPR91)has garnered widespread attention as a prospective therapeutic target for metabolic diseases.However,no structural data for human GPR91(hGPR91);detailed molecular mechanism of action(MOA)of GPR91 have been reported,with reported compounds targeting GPR91 limited.In this study,hGPR91 structures were constructed through homology modeling.High-affinity agonist compound 31 and antagonist NF-58-EJ40 were selected for investigation.By molecular dynamics(MD)simulations,we have elucidated MOA of GPR91 agonists and antagonists for the first time.We identified the crucial role of the D174FASSG sequence,the L652.46SVSD2.50 sequence and the N642.45-W1474.50 in maintaining GPR91’s inactive state conformation.Agonist binding disrupted constraints mediated by the aforementioned sequence,which led to significant outward movements of transmembrane helixes(TMs);repositioning of intracellular loop2(ICL2);ICL3,thereby forming an expanded cavity for G proteins binding.Furthermore,the pivotal role of the dicarboxylic acid structure of agonists in initiating signal transduction was confirmed.In contrast,antagonist binding stabilized these conformational constraints,resulting in relatively minor movements of TMs that were insufficient to generate a binding cavity large enough to accommodate the G protein.Clarifying MOA of GPR91 agonists and antagonists is crucial for guiding the design of relevant drugs.
