G protein-coupled receptors(GPCRs)are the largest family of membrane proteins in eukaryotes,with nearly 800 genes coding for these proteins.They are involved in many physiological processes,such as light perception,ta...G protein-coupled receptors(GPCRs)are the largest family of membrane proteins in eukaryotes,with nearly 800 genes coding for these proteins.They are involved in many physiological processes,such as light perception,taste and smell,neurotransmitter,metabolism,endocrine and exocrine,cell growth and migration.Importantly,GPCRs and their ligands are the targets of approximately one third of all marketed drugs.GPCRs are traditionally known for their role in transmitting signals from the extracellular environment to the cell's interior via the plasma membrane.However,emerging evidence suggests that GPCRs are also localized on mitochondria,where they play critical roles in modulating mitochondrial functions.These mitochondrial GPCRs(mGPCRs)can influence processes such as mitochondrial respiration,apoptosis,and reactive oxygen species(ROS)production.By interacting with mitochondrial signaling pathways,mGPCRs contribute to the regulation of energy metabolism and cell survival.Their presence on mitochondria adds a new layer of complexity to the understanding of cellular signaling,highlighting the organelle's role as not just an energy powerhouse but also a crucial hub for signal transduction.This expanding understanding of mGPCR function on mitochondria opens new avenues for research,particularly in the context of diseases where mitochondrial dysfunction plays a key role.Abnormalities in the phase conductance pathway of GPCRs located on mitochondria are closely associated with the development of systemic diseases such as cardiovascular disease,diabetes,obesity and Alzheimer's disease.In this review,we examined the various types of GPCRs identified on mitochondrial membranes and analyzed the complex relationships between mGPCRs and the pathogenesis of various diseases.We aim to provide a clearer understanding of the emerging significance of mGPCRs in health and disease,and to underscore their potential as therapeutic targets in the treatment of these conditions.展开更多
Sugar and protein are the major macronutrients＇ sources, and their balanced intake is important for animal＇s health. It has been observed that animals are able to change food preference in an imbalanced nutritional ...Sugar and protein are the major macronutrients＇ sources, and their balanced intake is important for animal＇s health. It has been observed that animals are able to change food preference in an imbalanced nutritional condition to selectively consume nutrients that are deficient in the body （Dethier, 1976）. Early studies in both Drosophila and mouse have demonstrated that animals exhibit food rejection to imbalanced diets lacking essential amino acids （Hao et al., 2005; Bjordal et al., 2014）. Furthermore, the food preference change upon protein depri- vation has been characterized using a two choice assay in Drosophila （Ribeiro and Dickson, 2010; Vargas et al., 2010）. Different from protein food, sugar is the main energy source, and sugar deficiency severely affects animal survival （Lee et al., 2008）. However, whether animals adopt a strategy of fast food preference switch upon sugar deprivation had not been investigated, and the neural mechanisms underlying this behavior regulation remain poorly understood.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
近日,中国科学院上海药物研究所徐华强/赵丽华团队联合山东大学于晓/孙金鹏团队、浙江大学基础医学院张岩团队等,在《自然-通讯》(Nature Communications)上,在线发表了题为"Structure insights into selective coupling of G prot...近日,中国科学院上海药物研究所徐华强/赵丽华团队联合山东大学于晓/孙金鹏团队、浙江大学基础医学院张岩团队等,在《自然-通讯》(Nature Communications)上,在线发表了题为"Structure insights into selective coupling of G protein subtypes by a class B Gprotein-coupled receptor"的研究成果.科研人员在揭示B类GPCRs一个亚家族的两个受体激素识别、受体激活和G蛋白偶联的特异性机制基础上,解析了CRF2R分别与Go蛋白和G11蛋白的复合物三维结构,即B类GPCRs偶联Go和G11的首个复合物结构,系统性阐述了促肾上腺皮质激素释放因子受体偶联Gs、G11和Go蛋白的分子作用机制,为B类GPCRs的G蛋白选择性偶联激活机制奠定了研究基础.展开更多
Adipogenesis is the healthy expansion of white adipose tissue(WAT),serving as a compensatory response to maintain metabolic homeostasis in the presence of excess energy in the body.Therefore,the identification of nove...Adipogenesis is the healthy expansion of white adipose tissue(WAT),serving as a compensatory response to maintain metabolic homeostasis in the presence of excess energy in the body.Therefore,the identification of novel regulatory molecules in adipogenesis,specifically membrane receptors such as G protein-coupled receptors(GPCRs),holds significant clinical promise.These receptors can serve as viable targets for pharmaceuticals,offering potential for restoring metabolic homeostasis in individuals with obesity.We utilized trajectory inference methods to analyze three distinct single-nucleus sequencing(sNuc-seq)datasets of adipose tissue and systematically identified GPCRs with the potential to regulate adipogenesis.Through verification in primary adipose progenitor cells(APCs)of mice,we discovered that ADGRD1 promoted the differentiation of APCs,while GPR39 inhibits this process.In the obese mouse model induced by a high-fat diet(HFD),both gain-of-function and loss-of-function studies validated that ADGRD1 promoted adipogenesis,thereby improving metabolic homeostasis,while GPR39 inhibited adipogenesis,leading to metabolic dysfunction.Additionally,through the analysis of 2,400 ChIP-seq data and 1,204 bulk RNA-seq data,we found that the transcription factors(TFs)MEF2D and TCF12 regulated the expression of ADGRD1 and GPR39,respectively.Our study revealed the regulatory role of GPCRs in adipogenesis,providing novel targets for clinical intervention of metabolic dysfunction in obese patients.展开更多
G-protein coupled receptors(GPCRs)are the largest family of druggable targets.In recent years,GPCR structural biology has made great advances,revealing the three-dimensional structures of many GPCRs and their interact...G-protein coupled receptors(GPCRs)are the largest family of druggable targets.In recent years,GPCR structural biology has made great advances,revealing the three-dimensional structures of many GPCRs and their interactions with ligands,proteins,and membrane components,which also have inspired a surge of structure-based drug discovery campaigns.This article provides a comprehensive summary of the currently available structural insights into the allosteric pockets of GPCRs and their regulatory mechanisms governing GPCR conformational changes.Furthermore,this article also presents several structure-inspired studies that utilize both orthosteric and allosteric modulation to discover small molecular modulators targeting GPCRs.The article emphasizes the promising potential of drug discovery targeting GPCR allosteric sites,while acknowledging the challenges arising from the limited structural information regarding the lipids and cholesterols in the membrane.Finally,the article discusses the future prospects of using large-scale or focused compound libraries to discover novel chemotypes,as well as the application of artificial intelligence(AI)in structure-based virtual screening(SBVS)against GPCRs.展开更多
Activating and inactivating mutations in numerous human G protein-coupled receptors(GPCRs)are associated with a wide range of disease phenotypes.Here we use several class A GPCRs with a particularly large set of ident...Activating and inactivating mutations in numerous human G protein-coupled receptors(GPCRs)are associated with a wide range of disease phenotypes.Here we use several class A GPCRs with a particularly large set of identified disease-associated mutations,many of which were biochemically characterized,along with known GPCR structures and current models of GPCR activation,to understand the molecular mechanisms yielding pathological phenotypes.Based on this mechanistic understanding we also propose different therapeutic approaches,both conventional,using small molecule ligands,and novel,involving gene therapy.展开更多
Understanding the cellular mechanisms of drug addiction remains a key task in current brain research.While neuron-based mechanisms have been extensively explored over the past three decades,recent evidence indicates a...Understanding the cellular mechanisms of drug addiction remains a key task in current brain research.While neuron-based mechanisms have been extensively explored over the past three decades,recent evidence indicates a critical involvement of astrocytes,the main type of non-neuronal cells in the brain.In response to extracellular stimuli,astrocytes modulate the activity of neurons,synaptic transmission,and neural network properties,collectively influencing brain function.G protein-coupled receptors(GPCRs)expressed on astrocyte surfaces respond to neuron-and environment-derived ligands by activating or inhibiting astrocytic signaling,which in turn regulates adjacent neurons and their circuitry.In this review,we focus on the dopamine D1 receptors(D1R)and metabotropic glutamate receptor 5(mGLUR5 or GRM5)—two GPCRs that have been critically implicated in the acquisition and maintenance of addiction-related behaviors.Positioned as an introductory-level review,this article briefly discusses astrocyte biology,outlines earlier discoveries about the role of astrocytes in substance-use disorders(SUDs),and provides detailed discussion about astrocytic D1Rs and mGLUR5s in regulating synapse and network functions in the nucleus accumbens(NAc)—a brain region that mediates addictionrelated emotional and motivational responses.This review serves as a stepping stone for readers of Engineering to explore links between astrocytic GPCRs and drug addiction and other psychiatric disorders.展开更多
Apelin受体APJ是加拿大学者O＇Dowd等于1993年发现的一种孤儿G蛋白偶联受体（orphan GPCRs,o GPCRs）,因其与血管紧张素Ⅱ1型受体（angiotensinl I typel receptor,ATI）有30%~50%的同源性,故取名为血管紧张素Ⅱ1型受体相关蛋白（putati...Apelin受体APJ是加拿大学者O＇Dowd等于1993年发现的一种孤儿G蛋白偶联受体（orphan GPCRs,o GPCRs）,因其与血管紧张素Ⅱ1型受体（angiotensinl I typel receptor,ATI）有30%~50%的同源性,故取名为血管紧张素Ⅱ1型受体相关蛋白（putative receptor protein related to the angiotensin II typel receptor,APJ）（[1]）。为探寻APJ内源性配体,日本学者Tatemoto于1998年用反向药理学方法,展开更多
基金supported the Fund of Sichuan Provincial Department of Science and Technology(Grant No.:2024YFFK0393)the CAMS Innovation Fund for Medical Sciences(CIFMS,Grant No.:2019-I2M-5-004).
文摘G protein-coupled receptors(GPCRs)are the largest family of membrane proteins in eukaryotes,with nearly 800 genes coding for these proteins.They are involved in many physiological processes,such as light perception,taste and smell,neurotransmitter,metabolism,endocrine and exocrine,cell growth and migration.Importantly,GPCRs and their ligands are the targets of approximately one third of all marketed drugs.GPCRs are traditionally known for their role in transmitting signals from the extracellular environment to the cell's interior via the plasma membrane.However,emerging evidence suggests that GPCRs are also localized on mitochondria,where they play critical roles in modulating mitochondrial functions.These mitochondrial GPCRs(mGPCRs)can influence processes such as mitochondrial respiration,apoptosis,and reactive oxygen species(ROS)production.By interacting with mitochondrial signaling pathways,mGPCRs contribute to the regulation of energy metabolism and cell survival.Their presence on mitochondria adds a new layer of complexity to the understanding of cellular signaling,highlighting the organelle's role as not just an energy powerhouse but also a crucial hub for signal transduction.This expanding understanding of mGPCR function on mitochondria opens new avenues for research,particularly in the context of diseases where mitochondrial dysfunction plays a key role.Abnormalities in the phase conductance pathway of GPCRs located on mitochondria are closely associated with the development of systemic diseases such as cardiovascular disease,diabetes,obesity and Alzheimer's disease.In this review,we examined the various types of GPCRs identified on mitochondrial membranes and analyzed the complex relationships between mGPCRs and the pathogenesis of various diseases.We aim to provide a clearer understanding of the emerging significance of mGPCRs in health and disease,and to underscore their potential as therapeutic targets in the treatment of these conditions.
基金supported by the grants from the National Science Foundation of China(Nos. 91132709 and 31130027)
文摘Sugar and protein are the major macronutrients＇ sources, and their balanced intake is important for animal＇s health. It has been observed that animals are able to change food preference in an imbalanced nutritional condition to selectively consume nutrients that are deficient in the body （Dethier, 1976）. Early studies in both Drosophila and mouse have demonstrated that animals exhibit food rejection to imbalanced diets lacking essential amino acids （Hao et al., 2005; Bjordal et al., 2014）. Furthermore, the food preference change upon protein depri- vation has been characterized using a two choice assay in Drosophila （Ribeiro and Dickson, 2010; Vargas et al., 2010）. Different from protein food, sugar is the main energy source, and sugar deficiency severely affects animal survival （Lee et al., 2008）. However, whether animals adopt a strategy of fast food preference switch upon sugar deprivation had not been investigated, and the neural mechanisms underlying this behavior regulation remain poorly understood.
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.
文摘近日,中国科学院上海药物研究所徐华强/赵丽华团队联合山东大学于晓/孙金鹏团队、浙江大学基础医学院张岩团队等,在《自然-通讯》(Nature Communications)上,在线发表了题为"Structure insights into selective coupling of G protein subtypes by a class B Gprotein-coupled receptor"的研究成果.科研人员在揭示B类GPCRs一个亚家族的两个受体激素识别、受体激活和G蛋白偶联的特异性机制基础上,解析了CRF2R分别与Go蛋白和G11蛋白的复合物三维结构,即B类GPCRs偶联Go和G11的首个复合物结构,系统性阐述了促肾上腺皮质激素释放因子受体偶联Gs、G11和Go蛋白的分子作用机制,为B类GPCRs的G蛋白选择性偶联激活机制奠定了研究基础.
基金supported by the National Natural Science Foundation of China(32270603,31925021,82130022,92357305,82341226,32271232)the National Key Research and Development Program of China(2021YFF1201100,2018YFA0800701)the Fundamental Research Funds for the Central Universities(BMU2021YJ057)。
文摘Adipogenesis is the healthy expansion of white adipose tissue(WAT),serving as a compensatory response to maintain metabolic homeostasis in the presence of excess energy in the body.Therefore,the identification of novel regulatory molecules in adipogenesis,specifically membrane receptors such as G protein-coupled receptors(GPCRs),holds significant clinical promise.These receptors can serve as viable targets for pharmaceuticals,offering potential for restoring metabolic homeostasis in individuals with obesity.We utilized trajectory inference methods to analyze three distinct single-nucleus sequencing(sNuc-seq)datasets of adipose tissue and systematically identified GPCRs with the potential to regulate adipogenesis.Through verification in primary adipose progenitor cells(APCs)of mice,we discovered that ADGRD1 promoted the differentiation of APCs,while GPR39 inhibits this process.In the obese mouse model induced by a high-fat diet(HFD),both gain-of-function and loss-of-function studies validated that ADGRD1 promoted adipogenesis,thereby improving metabolic homeostasis,while GPR39 inhibited adipogenesis,leading to metabolic dysfunction.Additionally,through the analysis of 2,400 ChIP-seq data and 1,204 bulk RNA-seq data,we found that the transcription factors(TFs)MEF2D and TCF12 regulated the expression of ADGRD1 and GPR39,respectively.Our study revealed the regulatory role of GPCRs in adipogenesis,providing novel targets for clinical intervention of metabolic dysfunction in obese patients.
基金This work is supported by Beijing Municipal Science&Technology Commission(Z201100005320012 to N.H.)and Tsinghua University.
文摘G-protein coupled receptors(GPCRs)are the largest family of druggable targets.In recent years,GPCR structural biology has made great advances,revealing the three-dimensional structures of many GPCRs and their interactions with ligands,proteins,and membrane components,which also have inspired a surge of structure-based drug discovery campaigns.This article provides a comprehensive summary of the currently available structural insights into the allosteric pockets of GPCRs and their regulatory mechanisms governing GPCR conformational changes.Furthermore,this article also presents several structure-inspired studies that utilize both orthosteric and allosteric modulation to discover small molecular modulators targeting GPCRs.The article emphasizes the promising potential of drug discovery targeting GPCR allosteric sites,while acknowledging the challenges arising from the limited structural information regarding the lipids and cholesterols in the membrane.Finally,the article discusses the future prospects of using large-scale or focused compound libraries to discover novel chemotypes,as well as the application of artificial intelligence(AI)in structure-based virtual screening(SBVS)against GPCRs.
基金This work was supported by NIH grants GM077561,EY011500,and GM109955(VVG)and DAAD RISE worldwide summer scholarship and Eberhard Karls Universitat Tubingen(Germany)Master’s program(HS).
文摘Activating and inactivating mutations in numerous human G protein-coupled receptors(GPCRs)are associated with a wide range of disease phenotypes.Here we use several class A GPCRs with a particularly large set of identified disease-associated mutations,many of which were biochemically characterized,along with known GPCR structures and current models of GPCR activation,to understand the molecular mechanisms yielding pathological phenotypes.Based on this mechanistic understanding we also propose different therapeutic approaches,both conventional,using small molecule ligands,and novel,involving gene therapy.
基金partially supported by the National Institutes of Health(NIH)grants DA056213(to Alexander K.Zinsmaier),DA053388(to Eric J.Nestler),DA023206(to Yan Dong),DA060868(to Yan Dong),and DA040620(to Eric J.Nestler and Yan Dong)。
文摘Understanding the cellular mechanisms of drug addiction remains a key task in current brain research.While neuron-based mechanisms have been extensively explored over the past three decades,recent evidence indicates a critical involvement of astrocytes,the main type of non-neuronal cells in the brain.In response to extracellular stimuli,astrocytes modulate the activity of neurons,synaptic transmission,and neural network properties,collectively influencing brain function.G protein-coupled receptors(GPCRs)expressed on astrocyte surfaces respond to neuron-and environment-derived ligands by activating or inhibiting astrocytic signaling,which in turn regulates adjacent neurons and their circuitry.In this review,we focus on the dopamine D1 receptors(D1R)and metabotropic glutamate receptor 5(mGLUR5 or GRM5)—two GPCRs that have been critically implicated in the acquisition and maintenance of addiction-related behaviors.Positioned as an introductory-level review,this article briefly discusses astrocyte biology,outlines earlier discoveries about the role of astrocytes in substance-use disorders(SUDs),and provides detailed discussion about astrocytic D1Rs and mGLUR5s in regulating synapse and network functions in the nucleus accumbens(NAc)—a brain region that mediates addictionrelated emotional and motivational responses.This review serves as a stepping stone for readers of Engineering to explore links between astrocytic GPCRs and drug addiction and other psychiatric disorders.
文摘Apelin受体APJ是加拿大学者O＇Dowd等于1993年发现的一种孤儿G蛋白偶联受体（orphan GPCRs,o GPCRs）,因其与血管紧张素Ⅱ1型受体（angiotensinl I typel receptor,ATI）有30%~50%的同源性,故取名为血管紧张素Ⅱ1型受体相关蛋白（putative receptor protein related to the angiotensin II typel receptor,APJ）（[1]）。为探寻APJ内源性配体,日本学者Tatemoto于1998年用反向药理学方法,
