Objectives:To investigate whether the protective actions of ginsenoside Rb1(Rb1)on astrocytes are mediated through the G_(s)-type G-protein-coupled receptor(GPCR-G_(s)).Methods:Primary astrocyte cultures derived from ...Objectives:To investigate whether the protective actions of ginsenoside Rb1(Rb1)on astrocytes are mediated through the G_(s)-type G-protein-coupled receptor(GPCR-G_(s)).Methods:Primary astrocyte cultures derived from neonatal mouse brain were used.Astrocyte injury was induced via oxygen-glucose deprivation/re-oxygenation(OGD/R).Cell morphology,viability,lactate dehydrogenase(LDH)leakage,apoptosis,glutamate uptake,and brain-derived neurotrophic factor(BDNF)secretion were assessed to gauge cell survival and functionality.Western blot was used to investigate the cyclic adenosine monophosphate(cAMP)and protein kinase B(Akt)signaling pathways.GPCR-G_(s)-specific inhibitors and molecular docking were used to identify target receptors.Results:Rb1 at concentrations ranging from 0.8 to 5μM did not significantly affect the viability,glutamate uptake,or BDNF secretion in normal astrocytes.OGD/R reduced astrocyte viability,increasing their LDH leakage and apoptosis rate.It also decreased glutamate uptake and BDNF secretion by these cells.Rb1 had protective effects of astrocytes challenged by OGD/R,by improving viability,reducing apoptosis,and enhancing glutamate uptake and BDNF secretion.Additionally,Rb1 activated the cAMP and Akt pathways in these cells.When the GPCR-G_(s) inhibitor NF449 was introduced,the protective effects of Rb1 completely disappeared,and its activation of cAMP and Akt signaling pathways was significantly inhibited.Conclusion:Rb1 protects against astrocytes from OGD/R-induced injury through GPCR-G_(s) mediation.展开更多
据Gour N 2024年2月13日[Immunity,2024,57(2):333-348.]报道,美国所罗门-H-斯奈德神经科学系研究人员通过研究中性粒细胞不同功能状态的机制,揭示了G蛋白偶联受体Mrgpra1信号在中性粒细胞中的关键作用,它控制着中性粒细胞在细菌性肺炎...据Gour N 2024年2月13日[Immunity,2024,57(2):333-348.]报道,美国所罗门-H-斯奈德神经科学系研究人员通过研究中性粒细胞不同功能状态的机制,揭示了G蛋白偶联受体Mrgpra1信号在中性粒细胞中的关键作用,它控制着中性粒细胞在细菌性肺炎期间的活化。该团队发现的一种平衡中性粒细胞反应的途径,可能成为预防和治疗难治性肺部感染的靶点。展开更多
Purine nucleotides are crucial for the effective operation of cell membrane proteins maintaining the neurotransmitter responses of 5-HT. Major protein targets in the treatment of depression include SERT, N/K ATPase an...Purine nucleotides are crucial for the effective operation of cell membrane proteins maintaining the neurotransmitter responses of 5-HT. Major protein targets in the treatment of depression include SERT, N/K ATPase and GPCR. Each protein target is responsive to a specific complement of drugs: antidepressants (SERT), lithium and cardiogenic steroids (N/K ATPase), 5-HT receptor ligands (GPCR). Computational software is useful for comparing molecular similarity within ligand-ligand and ligand-nucleotide structures. Previous studies demonstrate that GPCR ligands of different pharmacologic classes display relative molecular similarity to nucleotide structures. The current study applies this methodology to compound structures modulating SERT and N/K ATPase receptors. Minimum energy conformers of SERT antagonists demonstrate relative molecular similarity to the structural template of GTP nucleotide. GTP template fits of 5-HT and psilocin are similar, whereas a SERT-like fit is one of several for the ketamine structure. Endogenous and pharmaceutical modulators of Na/K ATPase relate to adenine nucleotide. The fits of cardiogenic steroids to a cGMP template demonstrate similarities and differences between compounds. Relative molecular similarity within the structures of hormones, drugs and nucleotides has implications for neurotransmitter transport and cell signal transduction processes.展开更多
Description Cellular membranes present natural borders for signal transduction between cells and their environment. Nature developed different strategies to enable signals to cross the membrane barrier. The goal of th...Description Cellular membranes present natural borders for signal transduction between cells and their environment. Nature developed different strategies to enable signals to cross the membrane barrier. The goal of this meeting is to discuss the molecular mechanisms of transmembrane signaling on the basis of three protein classes, i.e.展开更多
The superfamily of G protein-coupled receptors (GPCRs) contains immense structural and functional diversity and mediates a myriad of biological processes upon activation by various extracellular signals.Critical roles...The superfamily of G protein-coupled receptors (GPCRs) contains immense structural and functional diversity and mediates a myriad of biological processes upon activation by various extracellular signals.Critical roles of GPCRs have been established in bone development,remodeling,and disease.Multiple human GPCR mutations impair bone development or metabolism,resulting in osteopathologies.Here we summarize the disease phenotypes and dysfunctions caused by GPCR gene mutations in humans as well as by deletion in animals.To date,92 receptors (5 glutamate family,67 rhodopsin family,5 adhesion,4 frizzled/taste2 family,5 secretin family,and 6 other 7TM receptors) have been associated with bone diseases and dysfunctions (36 in humans and 72 in animals).By analyzing data from these 92 GPCRs,we found that mutation or deletion of different individual GPCRs could induce similar bone diseases or dysfunctions,and the same individual GPCR mutation or deletion could induce different bone diseases or dysfunctions in different populations or animal models.Data from human diseases or dysfunctions identified 19 genes whose mutation was associated with human BMD:9 genes each for human height and osteoporosis;4 genes each for human osteoarthritis (OA) and fracture risk;and 2 genes each for adolescent idiopathic scoliosis (AIS),periodontitis,osteosarcoma growth,and tooth development.Reports from gene knockout animals found 40 GPCRs whose deficiency reduced bone mass,while deficiency of 22 GPCRs increased bone mass and BMD;deficiency of 8 GPCRs reduced body length,while 5 mice had reduced femur size upon GPCR deletion.Furthermore,deficiency in 6 GPCRs induced osteoporosis;4 induced osteoarthritis;3 delayed fracture healing;3 reduced arthritis severity;and reduced bone strength,increased bone strength,and increased cortical thickness were each observed in 2 GPCR-deficiency models.The ever-expanding number of GPCR mutation-associated diseases warrants accelerated molecular analysis,population studies,and investigation of phenotype correlation with SNPs to elucidate GPCR function in human diseases.展开更多
基金supported by the grant International Cooperation Project of Prevention and Treatment of Major Diseases with Chinese Medicine(GZYYGJ2021047)the High-end Experts Support Program from the Ministry of Science and Technology(DL 2021110001L)the Basic Research Funds from the Ministry of Education(1000061223731).
文摘Objectives:To investigate whether the protective actions of ginsenoside Rb1(Rb1)on astrocytes are mediated through the G_(s)-type G-protein-coupled receptor(GPCR-G_(s)).Methods:Primary astrocyte cultures derived from neonatal mouse brain were used.Astrocyte injury was induced via oxygen-glucose deprivation/re-oxygenation(OGD/R).Cell morphology,viability,lactate dehydrogenase(LDH)leakage,apoptosis,glutamate uptake,and brain-derived neurotrophic factor(BDNF)secretion were assessed to gauge cell survival and functionality.Western blot was used to investigate the cyclic adenosine monophosphate(cAMP)and protein kinase B(Akt)signaling pathways.GPCR-G_(s)-specific inhibitors and molecular docking were used to identify target receptors.Results:Rb1 at concentrations ranging from 0.8 to 5μM did not significantly affect the viability,glutamate uptake,or BDNF secretion in normal astrocytes.OGD/R reduced astrocyte viability,increasing their LDH leakage and apoptosis rate.It also decreased glutamate uptake and BDNF secretion by these cells.Rb1 had protective effects of astrocytes challenged by OGD/R,by improving viability,reducing apoptosis,and enhancing glutamate uptake and BDNF secretion.Additionally,Rb1 activated the cAMP and Akt pathways in these cells.When the GPCR-G_(s) inhibitor NF449 was introduced,the protective effects of Rb1 completely disappeared,and its activation of cAMP and Akt signaling pathways was significantly inhibited.Conclusion:Rb1 protects against astrocytes from OGD/R-induced injury through GPCR-G_(s) mediation.
文摘据Gour N 2024年2月13日[Immunity,2024,57(2):333-348.]报道,美国所罗门-H-斯奈德神经科学系研究人员通过研究中性粒细胞不同功能状态的机制,揭示了G蛋白偶联受体Mrgpra1信号在中性粒细胞中的关键作用,它控制着中性粒细胞在细菌性肺炎期间的活化。该团队发现的一种平衡中性粒细胞反应的途径,可能成为预防和治疗难治性肺部感染的靶点。
文摘Purine nucleotides are crucial for the effective operation of cell membrane proteins maintaining the neurotransmitter responses of 5-HT. Major protein targets in the treatment of depression include SERT, N/K ATPase and GPCR. Each protein target is responsive to a specific complement of drugs: antidepressants (SERT), lithium and cardiogenic steroids (N/K ATPase), 5-HT receptor ligands (GPCR). Computational software is useful for comparing molecular similarity within ligand-ligand and ligand-nucleotide structures. Previous studies demonstrate that GPCR ligands of different pharmacologic classes display relative molecular similarity to nucleotide structures. The current study applies this methodology to compound structures modulating SERT and N/K ATPase receptors. Minimum energy conformers of SERT antagonists demonstrate relative molecular similarity to the structural template of GTP nucleotide. GTP template fits of 5-HT and psilocin are similar, whereas a SERT-like fit is one of several for the ketamine structure. Endogenous and pharmaceutical modulators of Na/K ATPase relate to adenine nucleotide. The fits of cardiogenic steroids to a cGMP template demonstrate similarities and differences between compounds. Relative molecular similarity within the structures of hormones, drugs and nucleotides has implications for neurotransmitter transport and cell signal transduction processes.
文摘Description Cellular membranes present natural borders for signal transduction between cells and their environment. Nature developed different strategies to enable signals to cross the membrane barrier. The goal of this meeting is to discuss the molecular mechanisms of transmembrane signaling on the basis of three protein classes, i.e.
基金supported by grants from the National Key Research and Development Program of China(2018YFC1105102 to J.L.,2016YFC0902102 to J.L.and J.X.)the National Natural Science Foundation of China(81722020,91749204,81472048 to J.L.,81330049 to M.L.,81330059 and 81572640 to J.X.)+2 种基金the Innovation Program of Shanghai Municipal Education Commission(14ZZ051 to J.L.,2017ZZ01017 to J.X.)the Science and Technology Commission of Shanghai Municipality(12ZR1447900 to J.L.,17JC1400903 and 17411950300 to J.X.)the Fundamental Research Funds for the Central Universities(to J.L.)
文摘The superfamily of G protein-coupled receptors (GPCRs) contains immense structural and functional diversity and mediates a myriad of biological processes upon activation by various extracellular signals.Critical roles of GPCRs have been established in bone development,remodeling,and disease.Multiple human GPCR mutations impair bone development or metabolism,resulting in osteopathologies.Here we summarize the disease phenotypes and dysfunctions caused by GPCR gene mutations in humans as well as by deletion in animals.To date,92 receptors (5 glutamate family,67 rhodopsin family,5 adhesion,4 frizzled/taste2 family,5 secretin family,and 6 other 7TM receptors) have been associated with bone diseases and dysfunctions (36 in humans and 72 in animals).By analyzing data from these 92 GPCRs,we found that mutation or deletion of different individual GPCRs could induce similar bone diseases or dysfunctions,and the same individual GPCR mutation or deletion could induce different bone diseases or dysfunctions in different populations or animal models.Data from human diseases or dysfunctions identified 19 genes whose mutation was associated with human BMD:9 genes each for human height and osteoporosis;4 genes each for human osteoarthritis (OA) and fracture risk;and 2 genes each for adolescent idiopathic scoliosis (AIS),periodontitis,osteosarcoma growth,and tooth development.Reports from gene knockout animals found 40 GPCRs whose deficiency reduced bone mass,while deficiency of 22 GPCRs increased bone mass and BMD;deficiency of 8 GPCRs reduced body length,while 5 mice had reduced femur size upon GPCR deletion.Furthermore,deficiency in 6 GPCRs induced osteoporosis;4 induced osteoarthritis;3 delayed fracture healing;3 reduced arthritis severity;and reduced bone strength,increased bone strength,and increased cortical thickness were each observed in 2 GPCR-deficiency models.The ever-expanding number of GPCR mutation-associated diseases warrants accelerated molecular analysis,population studies,and investigation of phenotype correlation with SNPs to elucidate GPCR function in human diseases.
