The calcium release channels/ryanodine receptors (RyRs) usually form 2-D regular lattice in the endoplasmic/sarcoplasmic reticulum membranes. Several inter-RyR coupling
Osteoarthritis(OA)is a prevalent degenerative joint disorder marked by chronic pain,inflammation,and cartilage loss,with current treatments limited to symptom relief.G protein-coupled receptors(GPCRs)play a pivotal ro...Osteoarthritis(OA)is a prevalent degenerative joint disorder marked by chronic pain,inflammation,and cartilage loss,with current treatments limited to symptom relief.G protein-coupled receptors(GPCRs)play a pivotal role in OA progression by regulating inflammation,chondrocyte survival,and matrix homeostasis.However,their multifaceted signaling,via G proteins orβ-arrestins,poses challenges for precise therapeutic targeting.Biased agonism,where ligands selectively activate specific GPCR pathways,emerges as a promising approach to optimize efficacy and reduce side effects.This review examines biased signaling in OAassociated GPCRs,including cannabinoid receptors(CB1,CB2),chemokine receptors(CCR2,CXCR4),protease-activated receptors(PAR-2),adenosine receptors(A1R,A2AR,A2BR,A3R),melanocortin receptors(MC1R,MC3R),bradykinin receptors(B2R),prostaglandin E2 receptors(EP-2,EP-4),and calcium-sensing receptors(CaSR).We analyze ligands in clinical trials and explore natural products from Traditional Chinese Medicine as potential biased agonists.These compounds,with diverse structures and bioactivities,offer novel therapeutic avenues.By harnessing biased agonism,this review underscores the potential for developing targeted,safer OA therapies that address its complex pathology,bridging molecular insights with clinical translation.展开更多
Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly atte...Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly attenuates carbon tetrachloride-induced liver fibrosis in rats by enhancing dopamine receptor D1 expression and activating the Hippo signaling pathway,leading to phosphorylation and inactivation of yes-associated protein 1.This discovery links Gprotein-coupled receptor signaling to Hippo pathway regulation in hepatic fibrosis.The work highlights the dopamine receptor D1-Hippo/yes-associated protein 1 axis as a promising antifibrotic mechanism and introduces levodopa as a potential repurposing candidate for chronic liver disease.With its established safety and affordability,levodopa offers a rapidly translatable strategy that warrants validation in human tissues and diverse fibrosis models.Here,we place these findings in the broader context of G-protein-coupled receptor regulation of hepatic stellate cell activation,discuss translational opportunities for levodopa in liver fibrosis,and propose future directions to validate this pathway across disease models and clinical settings.展开更多
Insufficient sleep has been correlated to many physiological and psychoneurological disorders.Over the years,our understanding of the state of sleep has transcended from an inactive period of rest to a more active sta...Insufficient sleep has been correlated to many physiological and psychoneurological disorders.Over the years,our understanding of the state of sleep has transcended from an inactive period of rest to a more active state involving important cellular and molecular processes.In addition,during sleep,electrophysiological changes also occur in pathways in specific regions of the mammalian central nervous system(CNS).Activity mediated synaptic plasticity in the CNS can lead to long-term and sometimes permanent strengthening and/or weakening synaptic strength affecting neuronal network behaviour.Memory consolidation and learning that take place during sleep cycles,can be affected by changes in synaptic plasticity during sleep disturbances.G-protein coupled receptors(GPCRs),with their versatile structural and functional attributes,can regulate synaptic plasticity in CNS and hence,may be potentially affected in sleep deprived conditions.In this review,we aim to discuss important functional changes that can take place in the CNS during sleep and sleep deprivation and how changes in GPCRs can lead to potential problems with therapeutics with pharmacological interventions.展开更多
The renal handling of Na^(+) balance is a major determinant of the blood pressure(BP) level. The inability of the kidney to excrete the daily load of Na+ represents the primary cause of chronic hypertension. Among the...The renal handling of Na^(+) balance is a major determinant of the blood pressure(BP) level. The inability of the kidney to excrete the daily load of Na+ represents the primary cause of chronic hypertension. Among the different segments that constitute the nephron, those present in the distal part(i.e., the cortical thick ascending limb, the distal convoluted tubule, the connecting and collecting tubules) play a central role in the fine-tuning of renal Na^(+) excretion and are the target of many different regulatory processes that modulate Na^+ retention more or less efficiently. G-protein coupled receptors(GPCRs) are crucially involved in this regulation and could represent efficient pharmacological targets to control BP levels. In this review, we describe both classical and novel GPCR-dependent regulatory systems that have been shown to modulate renal Na^(+) absorption in the distal nephron. In addition to the multiplicity of the GPCR that regulate Na^(+) excretion, this review also highlights the complexity of these different pathways, and the connections between them.展开更多
Protein to protein interactions leading to homo/heteromerization of receptor is well documented in literature. These interactions leading to dimeric/oligomers formation of receptors are known to modulate their functio...Protein to protein interactions leading to homo/heteromerization of receptor is well documented in literature. These interactions leading to dimeric/oligomers formation of receptors are known to modulate their function, particularly in case of G-protein coupled receptors. The opioid receptor heteromers having changed pharmacological properties than the constituent protomers provides preferences for novel drug targets that could lead to potential analgesicactivity devoid of tolerance and physical dependence. Heterodimerization of opioid receptors appears to generate novel binding properties with improved specificity and lack of side effects. Further the molecules which can interact simultaneously to both the protomers of the heteromer, or to both the binding sites(orthosteric and allosteric) of a receptor protein could be potential therapeutic molecules. This review highlights the recent advancements in exploring the plausible role of heteromerization of opioid receptors in induction of tolerance free antinociception.展开更多
We studied the activation of β2-adrenergic receptor（β2AR） by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics（MD） simulation. The simulation was done on the assumption that β...We studied the activation of β2-adrenergic receptor（β2AR） by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics（MD） simulation. The simulation was done on the assumption that β2AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature. So the result should be close to that under the physiological conditions. We calculated the structure of binding sites in β2AR for the three ac- tivators. We also simulated the change of the conformation ofβ2AR in the transmembrane regions（TMs）, in the mo- lecular switches, and in the conserved DRY（Aspartic acid, Arginine and Tyrosine） motif. This study provides detailed information concerning the structure ofβ2AR during activation process.展开更多
G protein-coupled receptors(GPCRs)are the largest protein superfamily in the body,expressed in various tissues and organs,and are currently one of the most important clinical drug targets.Recently,a class of GPCRs wit...G protein-coupled receptors(GPCRs)are the largest protein superfamily in the body,expressed in various tissues and organs,and are currently one of the most important clinical drug targets.Recently,a class of GPCRs without endogenous ligands(orphan GPCRs)have been discovered.They exhibit different physiological functions in the body and act extensively on the cardiovascular and cerebrovascular systems.Among them,G protein-coupled receptor 124(GPR124)is an orphaned member of the G protein coupled receptor adhesion family that has attracted much attention.It plays a key role in promoting cerebral angiogenesis and maintaining the stability of the blood-brain barrier.It also associated with cardiovascular and cerebrovascular diseases such as cerebral ischemia and atherosclerosis.However,the role of GPR124 in these diseases,the associated signaling pathways,and possible drug intervention targets are still unclear.This article summarizes the physiological effects,pharmacological effects and related signal pathways of GPR124 published in the field of cardiovascular and cerebrovascular diseases published in recent years,in order to provide a reference for the study of the role of GPR124 in the occurrence and development of diseases.展开更多
In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of...In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.展开更多
Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system.These past 20 years had revealed that orexins/receptors s...Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system.These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation,intestinal motility,hormone secretion,lipolyze and reproduction functions.Associated to these peripheral functions,it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation,metabolic syndrome and cancers.The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease,multiple sclerosis and septic shock,obesity and digestive cancers.展开更多
The dopamine hypothesis of how antipsychotic drugs exert their beneficial effect in psychotic illness has an interesting history that dates back to 1950.This hypothesis is not to be confused with the dopamine hypothes...The dopamine hypothesis of how antipsychotic drugs exert their beneficial effect in psychotic illness has an interesting history that dates back to 1950.This hypothesis is not to be confused with the dopamine hypothesis of schizophrenia;the aim of the latter is to explain the etiology of schizophrenia.The present review does not deal with schizophrenia but,rather,with the historical development of our current understanding of the dopamine-associated actions of the drugs that reduce the symptoms of psychosis.This historical review begins with the serendipitous discovery of chlorpromazine,a drug synthesized around a chemical core that initially served to produce man-made dyes.This molecular core subsequently contributed to the chemistry of antihistamines.It was with the aim of producing a superior antihistamine that chlorpromazine was synthesized;instead,it revolutionized the treatment of psychosis.The first hypothesis of how this drug worked was that it induced hypothermia,a cooling of the body that led to a tranquilization of the mind.The new,at the time,discoveries of the presence of chemical transmitters in the brain soon steered investigations away from a temperature-related hypothesis toward questioning how this drug,and other drugs with similar properties and effects,modulated endogenous neurotransmission.As a result,over the years,researchers from around the world have begun to progressively learn what antipsychotic drugs do in the brain.展开更多
AIMTo investigate the therapeutic potential of tesevatinib （TSV）, a unique multi-kinase inhibitor currently in Phase Ⅱ clinical trials for autosomal dominant polycystic kidney disease （ADPKD）, in well-defined rod...AIMTo investigate the therapeutic potential of tesevatinib （TSV）, a unique multi-kinase inhibitor currently in Phase Ⅱ clinical trials for autosomal dominant polycystic kidney disease （ADPKD）, in well-defined rodent models of autosomal recessive polycystic kidney disease （ARPKD）. METHODSWe administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day（PN） 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model （from PN30 to PN90） to assess effcacy and toxicity in animals where developmental processes are complete. The following parameters were assessed： Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by： Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis （active VEGFR2/KDR） was assessed by Western analysis.RESULTSThis study demonstrates that： （1） in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis： EGFR, ErbB2, c-Src and KDR; and （2） this reduction of kinase activity resulted in signifcant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity.CONCLUSIONThe data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.展开更多
EMR2 is an EGF-like module containing mucin-like hormone receptor-2 precursor, a G-protein coupled receptor （G-PCR）. Mutation in EMR2 causes complicated disorders like polycystic kidney disease （PKD）. The structur...EMR2 is an EGF-like module containing mucin-like hormone receptor-2 precursor, a G-protein coupled receptor （G-PCR）. Mutation in EMR2 causes complicated disorders like polycystic kidney disease （PKD）. The structure of EMR2 shows that the fifth domain is comprised of EGF-TM7 helices. Functional assignment of EMR2 by support vector machine （SVM） revealed that along with transporter activity, several novel functions are predicted. A twenty amino acid sequence ＂MGGRVFLVFLAFCVWLTLPG＂ acts as the signal peptide responsible for post- translational transport. Eight amino acids are involved in N-glycosylation sites and two cleavage sites are LeuS17 and SerS18 in EMR2. The residue Arg241 is responsible for interaction with glycosaminoglycan and chondroitin sulfate. On the basis of structure, function and ligand binding sites, competitive EMR2 inhibitors designed may decrease the rate of human diseases like Usher＇s syndrome, bilateral frontoparietal polymicrogyria and PKD.展开更多
Hepatic fibrosis is a consequence of chronic liver disease,which can lead to cirrhosis and liver failure.There is no Food and Drugs Administration approved therapy for liver fibrosis to date;hence,identifying effectiv...Hepatic fibrosis is a consequence of chronic liver disease,which can lead to cirrhosis and liver failure.There is no Food and Drugs Administration approved therapy for liver fibrosis to date;hence,identifying effective therapeutic targets is an urgent need.Hepatic macrophages play a critical role in both initiation and progression of fibrosis.While resident liver macrophages,Kupffer cells are considered more anti-inflammatory,recent view has demonstrated that monocyte-derived macrophages(MoMs)are more pro-inflammatory and pro-fibrogenic[1].Moreover,MoMs exhibit more plasticity and undergo M1/M2“polarization”.The research by Zhang et al.[2]identified GPR65 signaling as a novel mechanism responsible for hepatic macrophage M1 polarization during liver injury and fibrosis.Notably,the role of this receptor in modulating inflammatory responses by various cells in other tissues has been previously reported[3].However,the role of GPR65 in liver inflammation and fibrosis has not been examined until now.展开更多
The MAS-related G protein-coupled receptor-X2(MRGPRX2),an orphan receptor expressed on mast cells(MCs),is upregulated upon inflammation and induces hypersensitivity and inflammatory diseases.In contrast to the large n...The MAS-related G protein-coupled receptor-X2(MRGPRX2),an orphan receptor expressed on mast cells(MCs),is upregulated upon inflammation and induces hypersensitivity and inflammatory diseases.In contrast to the large number of MRGPRX2 agonists,only a few antagonists have been described,and no optimization has been reported to improve potency,selectivity,and drug-like properties.Antagonists with ancillary inhibition of the putative mouse ortholog MRGPRB2 have not been described.Here,we present a multi-disciplinary approach involving chemistry,biology,and computational science,resulting in the development of a smallmolecule MRGPRX2 antagonist(PSB-172656,3-ethyl-7,8-difluoro-2-isopropylbenzo[4,5]imidazo[1,2-a]pyrimidin-4(1H)-one)based on a fragment screening hit.The compound exhibits metabolic stability,low cytotoxicity,and competitive blockade of MRGPRX2 activation induced by a diverse range of agonists.It displays subnanomolar potency in Ca2+mobilization assays(Ki value 0.142 nM)and was found to block MRGPRX2-mediated Gαq and Gαi1 dissociation,in addition toβ-arrestin-2 recruitment.PSB-172656 is selective for MRGPRX2 versus all other MRGPRX subtypes.Its effect on MCs was confirmed in cell lines,including rat basophilic leukemia cells(RBL-2H3)recombinantly expressing human MRGPRX2,human Laboratory of Allergic Diseases 2(LAD2)MCs,and native human skin MCs.PSB-172656 was found to additionally block the putative mouse ortholog of MRGPRX2,MRGPRB2,as determined in Ca2+mobilization assays(Ki 0.302 nM),and to prevent mouse tracheal contractions,local allergic reactions,and systemic anaphylactic symptoms.PSB-172656 constitutes a unique pharmacological tool and has the potential to be developed as a drug for mast cell-mediated hypersensitivity reactions and chronic inflammatory diseases,addressing a huge unmet medical need.展开更多
In a study published recently in Nature,Sass,Ma,and colleagues describe the neurokinin 2 receptor(NK2R),a G protein-coupled receptor(GPCR),as a novel regulator of food intake as well as energy expenditure,and develop ...In a study published recently in Nature,Sass,Ma,and colleagues describe the neurokinin 2 receptor(NK2R),a G protein-coupled receptor(GPCR),as a novel regulator of food intake as well as energy expenditure,and develop and characterize selective agonists that effectively activate NK2R to promote weight loss.Most interestingly,the authors bridge the gap between rodents and primates,raising hopes for novel treatment options.1 Although obesity cases are continuously rising,thereby contributing to major health problems,long-term effective treatment options are still limited.However,it is well established that GPCRs and their pathways are involved in the regulation of different processes controlling appetite,food intake,or energy homeostasis.Thus,several receptors expressed in neurons governing food intake have been proposed to be promising targets for body weight reduction.However,currently the only GPCR agonists approved for obesity treatment are targeting incretin receptors(receptors for glucagon-like peptide-1(GLP1R),glucose-dependent insulinotropic peptide(GIP),glucagon(GCGR))(Fig.1).展开更多
The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively s...The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy(PH) model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids(BAs) are ligands of farnesoid X receptor(FXR), a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potentialuse of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration.展开更多
Background OGR1 was found as a G-protein coupled receptor （GPCR） and proton sensor. Our previous studies have found that OGR1 has inhibitory effect on the metastasis of prostate cancer. In order to investigate the r...Background OGR1 was found as a G-protein coupled receptor （GPCR） and proton sensor. Our previous studies have found that OGR1 has inhibitory effect on the metastasis of prostate cancer. In order to investigate the roles of OGR1 gene in the biological activities of ovarian cancer, we studied the OGR1 effects on ovarian cancer cells, HEY cells.Methods OGR1 gene was transfected into HEY cell, in which endogenous expression is low. OGR1-overxepressed cells and vector-transfected cells were compared in different assays. Western blotting was employed to confirm the high expression level of OGR1. Cell proliferation was determined by MTT assay and cell doubling time assay. Cell migration assay （transwell assay） and cell adhesion assay were performed to determine the migration and adhesion potential of cells. Student＇s t test was employed for statistical analysis.Results Proliferation of OGR1-overexpressed cells was significantly reduced （P ＜0.01）; cell migration was significantly inhibited in the OGR1-transfected cells （P ＜0.01）; cell adhesion to extracellular matrix including fibronectin, vitronectin,collagen Ⅰ/Ⅳ was significantly increased （P ＜0.01）.Conclusions OGR1 expression in human ovarian cancer cells significantly inhibited the cell proliferation and migration,but significantly enhanced cell adhesion to the extracellular matrix. It indicated that OGR1 may be a tumor suppressor gene for ovarian cancer.展开更多
Canonical transient receptor potential 4(TRPC4) forms non-selective cation channels that contribute to phospholipase C-dependent Ca2+ entry into cells following stimulation of G protein coupled receptors and receptor ...Canonical transient receptor potential 4(TRPC4) forms non-selective cation channels that contribute to phospholipase C-dependent Ca2+ entry into cells following stimulation of G protein coupled receptors and receptor tyrosine kinases.Moreover,the channels are regulated by pertussis toxin-sensitive Gi/o proteins,lipids,and various other signaling mechanisms.TRPC4-containing channels participate in the regulation of a variety of physiological functions,including excitability of both gastrointestinal smooth muscles and brain neurons.This review is to present recent advances in the understanding of physiology and development of small molecular modulators of TRPC4 channels.展开更多
Fungal G-protein coupled receptors(GPCRs)play essential roles in sensing environmental cues including host signals.The study of GPCR in mediating fungus-insect interactions is still limited.Here we report the evolutio...Fungal G-protein coupled receptors(GPCRs)play essential roles in sensing environmental cues including host signals.The study of GPCR in mediating fungus-insect interactions is still limited.Here we report the evolution of GPCR genes encoded in the entomopathogenic Metarhizium species and found the expansion of Pth11-like GPCRs in the generalist species with a wide host range.By deletion of ten candidate genes MrGpr1–MrGpr10 selected from the six obtained subfamilies in the generalist M.robertsii,we found that each of them played a varied level of roles in mediating appressorium formation.In particular,deletion of MrGpr8 resulted in the failure of appressorium formation on different substrates and the loss of virulence during topical infection of insects but not during injection assays when compared with the wild-type(WT)strain.Further analysis revealed that disruption of MrGpr8 substantially impaired the nucleus translocation of the mitogen-activated protein kinase(MAPK)Mero-Fus3 but not the MAPK Mero-Slt2 during appressorium formation.We also found that the defect ofΔMrGpr8 could not be rescued with the addition of cyclic AMP for appressorium formation.Relative to the WT,differential expression of the selected genes have also been detected inΔMrGpr8.The results of this study may benefit the understanding of fungus-interactions mediated by GPCRs.展开更多
文摘The calcium release channels/ryanodine receptors (RyRs) usually form 2-D regular lattice in the endoplasmic/sarcoplasmic reticulum membranes. Several inter-RyR coupling
基金supported by the National Key R&D Program of the Ministry of Science and Technology(2023YFC2509900)National Natural Science Foundation of China(82374106)+3 种基金National Natural Science Foundation of China(U22A20371)the Basic and Applied Basic Research Fund of Guangdong Province(2021B1515120061)the Shenzhen Science and Technology Innovation Committee(JCYJ20210324102006017)SZ-HK Joint Laboratory for Innovative Biomaterials under CAS-HK Joint Laboratories(2024-2028).
文摘Osteoarthritis(OA)is a prevalent degenerative joint disorder marked by chronic pain,inflammation,and cartilage loss,with current treatments limited to symptom relief.G protein-coupled receptors(GPCRs)play a pivotal role in OA progression by regulating inflammation,chondrocyte survival,and matrix homeostasis.However,their multifaceted signaling,via G proteins orβ-arrestins,poses challenges for precise therapeutic targeting.Biased agonism,where ligands selectively activate specific GPCR pathways,emerges as a promising approach to optimize efficacy and reduce side effects.This review examines biased signaling in OAassociated GPCRs,including cannabinoid receptors(CB1,CB2),chemokine receptors(CCR2,CXCR4),protease-activated receptors(PAR-2),adenosine receptors(A1R,A2AR,A2BR,A3R),melanocortin receptors(MC1R,MC3R),bradykinin receptors(B2R),prostaglandin E2 receptors(EP-2,EP-4),and calcium-sensing receptors(CaSR).We analyze ligands in clinical trials and explore natural products from Traditional Chinese Medicine as potential biased agonists.These compounds,with diverse structures and bioactivities,offer novel therapeutic avenues.By harnessing biased agonism,this review underscores the potential for developing targeted,safer OA therapies that address its complex pathology,bridging molecular insights with clinical translation.
基金Supported by Open Project Fund of Henan Provincial Research Center for Precision Diagnosis and Treatment of Pulmonary Diseases Based on Multi-omics,No.DZXGCZXKF04.
文摘Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly attenuates carbon tetrachloride-induced liver fibrosis in rats by enhancing dopamine receptor D1 expression and activating the Hippo signaling pathway,leading to phosphorylation and inactivation of yes-associated protein 1.This discovery links Gprotein-coupled receptor signaling to Hippo pathway regulation in hepatic fibrosis.The work highlights the dopamine receptor D1-Hippo/yes-associated protein 1 axis as a promising antifibrotic mechanism and introduces levodopa as a potential repurposing candidate for chronic liver disease.With its established safety and affordability,levodopa offers a rapidly translatable strategy that warrants validation in human tissues and diverse fibrosis models.Here,we place these findings in the broader context of G-protein-coupled receptor regulation of hepatic stellate cell activation,discuss translational opportunities for levodopa in liver fibrosis,and propose future directions to validate this pathway across disease models and clinical settings.
基金Supported by Canadian Institutes of Health Research Grant,No.TGS-1092194-Year Fellowship from the University of British Columbia.
文摘Insufficient sleep has been correlated to many physiological and psychoneurological disorders.Over the years,our understanding of the state of sleep has transcended from an inactive period of rest to a more active state involving important cellular and molecular processes.In addition,during sleep,electrophysiological changes also occur in pathways in specific regions of the mammalian central nervous system(CNS).Activity mediated synaptic plasticity in the CNS can lead to long-term and sometimes permanent strengthening and/or weakening synaptic strength affecting neuronal network behaviour.Memory consolidation and learning that take place during sleep cycles,can be affected by changes in synaptic plasticity during sleep disturbances.G-protein coupled receptors(GPCRs),with their versatile structural and functional attributes,can regulate synaptic plasticity in CNS and hence,may be potentially affected in sleep deprived conditions.In this review,we aim to discuss important functional changes that can take place in the CNS during sleep and sleep deprivation and how changes in GPCRs can lead to potential problems with therapeutics with pharmacological interventions.
文摘The renal handling of Na^(+) balance is a major determinant of the blood pressure(BP) level. The inability of the kidney to excrete the daily load of Na+ represents the primary cause of chronic hypertension. Among the different segments that constitute the nephron, those present in the distal part(i.e., the cortical thick ascending limb, the distal convoluted tubule, the connecting and collecting tubules) play a central role in the fine-tuning of renal Na^(+) excretion and are the target of many different regulatory processes that modulate Na^+ retention more or less efficiently. G-protein coupled receptors(GPCRs) are crucially involved in this regulation and could represent efficient pharmacological targets to control BP levels. In this review, we describe both classical and novel GPCR-dependent regulatory systems that have been shown to modulate renal Na^(+) absorption in the distal nephron. In addition to the multiplicity of the GPCR that regulate Na^(+) excretion, this review also highlights the complexity of these different pathways, and the connections between them.
基金Supported by Council of Scientific and Industrial Research
文摘Protein to protein interactions leading to homo/heteromerization of receptor is well documented in literature. These interactions leading to dimeric/oligomers formation of receptors are known to modulate their function, particularly in case of G-protein coupled receptors. The opioid receptor heteromers having changed pharmacological properties than the constituent protomers provides preferences for novel drug targets that could lead to potential analgesicactivity devoid of tolerance and physical dependence. Heterodimerization of opioid receptors appears to generate novel binding properties with improved specificity and lack of side effects. Further the molecules which can interact simultaneously to both the protomers of the heteromer, or to both the binding sites(orthosteric and allosteric) of a receptor protein could be potential therapeutic molecules. This review highlights the recent advancements in exploring the plausible role of heteromerization of opioid receptors in induction of tolerance free antinociception.
基金Supported by the Young and Middle-Aged Scientists Research Awards Foundation of Shangdong Province,China(No.BS2011SW002)the Research Foundation for Advanced Talents of Ludong University,China(No.LY2011017)
文摘We studied the activation of β2-adrenergic receptor（β2AR） by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics（MD） simulation. The simulation was done on the assumption that β2AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature. So the result should be close to that under the physiological conditions. We calculated the structure of binding sites in β2AR for the three ac- tivators. We also simulated the change of the conformation ofβ2AR in the transmembrane regions（TMs）, in the mo- lecular switches, and in the conserved DRY（Aspartic acid, Arginine and Tyrosine） motif. This study provides detailed information concerning the structure ofβ2AR during activation process.
基金Natural Science Foundation of China(No.81960663,81860640)Key Project of Education Department of Hainan Province(No.Hnky2019ZD-25)。
文摘G protein-coupled receptors(GPCRs)are the largest protein superfamily in the body,expressed in various tissues and organs,and are currently one of the most important clinical drug targets.Recently,a class of GPCRs without endogenous ligands(orphan GPCRs)have been discovered.They exhibit different physiological functions in the body and act extensively on the cardiovascular and cerebrovascular systems.Among them,G protein-coupled receptor 124(GPR124)is an orphaned member of the G protein coupled receptor adhesion family that has attracted much attention.It plays a key role in promoting cerebral angiogenesis and maintaining the stability of the blood-brain barrier.It also associated with cardiovascular and cerebrovascular diseases such as cerebral ischemia and atherosclerosis.However,the role of GPR124 in these diseases,the associated signaling pathways,and possible drug intervention targets are still unclear.This article summarizes the physiological effects,pharmacological effects and related signal pathways of GPR124 published in the field of cardiovascular and cerebrovascular diseases published in recent years,in order to provide a reference for the study of the role of GPR124 in the occurrence and development of diseases.
基金supported by SIP-IPN,CONACYT (CB-168116)FIS/IMSS (FIS/IMSS/PROT/G11-2/1013)
文摘In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.
基金INSERM U1149/The Inflammation Research Center,Inserm Transfert,The Institut National du Cancer,No.2013-213Ligue Nationale Contre le Cancer,No.R16020HH,GB/MA/CD/EP-12062and AgroParisTech(INRAE and UniversitéParis-Saclay).
文摘Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system.These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation,intestinal motility,hormone secretion,lipolyze and reproduction functions.Associated to these peripheral functions,it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation,metabolic syndrome and cancers.The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease,multiple sclerosis and septic shock,obesity and digestive cancers.
文摘The dopamine hypothesis of how antipsychotic drugs exert their beneficial effect in psychotic illness has an interesting history that dates back to 1950.This hypothesis is not to be confused with the dopamine hypothesis of schizophrenia;the aim of the latter is to explain the etiology of schizophrenia.The present review does not deal with schizophrenia but,rather,with the historical development of our current understanding of the dopamine-associated actions of the drugs that reduce the symptoms of psychosis.This historical review begins with the serendipitous discovery of chlorpromazine,a drug synthesized around a chemical core that initially served to produce man-made dyes.This molecular core subsequently contributed to the chemistry of antihistamines.It was with the aim of producing a superior antihistamine that chlorpromazine was synthesized;instead,it revolutionized the treatment of psychosis.The first hypothesis of how this drug worked was that it induced hypothermia,a cooling of the body that led to a tranquilization of the mind.The new,at the time,discoveries of the presence of chemical transmitters in the brain soon steered investigations away from a temperature-related hypothesis toward questioning how this drug,and other drugs with similar properties and effects,modulated endogenous neurotransmission.As a result,over the years,researchers from around the world have begun to progressively learn what antipsychotic drugs do in the brain.
基金Supported by The PKD research program is provided by the Children’s Research Institute,the Lillian Goldman Charitable Trust,Ellsworth FamilyChildren’s Foundation of Children’s Hospital and Health System of Wisconsin
文摘AIMTo investigate the therapeutic potential of tesevatinib （TSV）, a unique multi-kinase inhibitor currently in Phase Ⅱ clinical trials for autosomal dominant polycystic kidney disease （ADPKD）, in well-defined rodent models of autosomal recessive polycystic kidney disease （ARPKD）. METHODSWe administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day（PN） 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model （from PN30 to PN90） to assess effcacy and toxicity in animals where developmental processes are complete. The following parameters were assessed： Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by： Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis （active VEGFR2/KDR） was assessed by Western analysis.RESULTSThis study demonstrates that： （1） in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis： EGFR, ErbB2, c-Src and KDR; and （2） this reduction of kinase activity resulted in signifcant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity.CONCLUSIONThe data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.
基金supported by the project "Establishment of Biomedical Informatics Center at RMRIRMS,Patan" by ICMR (Govt. of India),New Delhi
文摘EMR2 is an EGF-like module containing mucin-like hormone receptor-2 precursor, a G-protein coupled receptor （G-PCR）. Mutation in EMR2 causes complicated disorders like polycystic kidney disease （PKD）. The structure of EMR2 shows that the fifth domain is comprised of EGF-TM7 helices. Functional assignment of EMR2 by support vector machine （SVM） revealed that along with transporter activity, several novel functions are predicted. A twenty amino acid sequence ＂MGGRVFLVFLAFCVWLTLPG＂ acts as the signal peptide responsible for post- translational transport. Eight amino acids are involved in N-glycosylation sites and two cleavage sites are LeuS17 and SerS18 in EMR2. The residue Arg241 is responsible for interaction with glycosaminoglycan and chondroitin sulfate. On the basis of structure, function and ligand binding sites, competitive EMR2 inhibitors designed may decrease the rate of human diseases like Usher＇s syndrome, bilateral frontoparietal polymicrogyria and PKD.
文摘Hepatic fibrosis is a consequence of chronic liver disease,which can lead to cirrhosis and liver failure.There is no Food and Drugs Administration approved therapy for liver fibrosis to date;hence,identifying effective therapeutic targets is an urgent need.Hepatic macrophages play a critical role in both initiation and progression of fibrosis.While resident liver macrophages,Kupffer cells are considered more anti-inflammatory,recent view has demonstrated that monocyte-derived macrophages(MoMs)are more pro-inflammatory and pro-fibrogenic[1].Moreover,MoMs exhibit more plasticity and undergo M1/M2“polarization”.The research by Zhang et al.[2]identified GPR65 signaling as a novel mechanism responsible for hepatic macrophage M1 polarization during liver injury and fibrosis.Notably,the role of this receptor in modulating inflammatory responses by various cells in other tissues has been previously reported[3].However,the role of GPR65 in liver inflammation and fibrosis has not been examined until now.
基金supported by research grants from BMBF(German Federal Ministry for Education and Research)within the“Neuroallianz”consortium of the BioPharma initiativeby the Bonn International Graduate School of Drug Sciencessupported by the US National Institutes of Health grant#R01AI149487.
文摘The MAS-related G protein-coupled receptor-X2(MRGPRX2),an orphan receptor expressed on mast cells(MCs),is upregulated upon inflammation and induces hypersensitivity and inflammatory diseases.In contrast to the large number of MRGPRX2 agonists,only a few antagonists have been described,and no optimization has been reported to improve potency,selectivity,and drug-like properties.Antagonists with ancillary inhibition of the putative mouse ortholog MRGPRB2 have not been described.Here,we present a multi-disciplinary approach involving chemistry,biology,and computational science,resulting in the development of a smallmolecule MRGPRX2 antagonist(PSB-172656,3-ethyl-7,8-difluoro-2-isopropylbenzo[4,5]imidazo[1,2-a]pyrimidin-4(1H)-one)based on a fragment screening hit.The compound exhibits metabolic stability,low cytotoxicity,and competitive blockade of MRGPRX2 activation induced by a diverse range of agonists.It displays subnanomolar potency in Ca2+mobilization assays(Ki value 0.142 nM)and was found to block MRGPRX2-mediated Gαq and Gαi1 dissociation,in addition toβ-arrestin-2 recruitment.PSB-172656 is selective for MRGPRX2 versus all other MRGPRX subtypes.Its effect on MCs was confirmed in cell lines,including rat basophilic leukemia cells(RBL-2H3)recombinantly expressing human MRGPRX2,human Laboratory of Allergic Diseases 2(LAD2)MCs,and native human skin MCs.PSB-172656 was found to additionally block the putative mouse ortholog of MRGPRX2,MRGPRB2,as determined in Ca2+mobilization assays(Ki 0.302 nM),and to prevent mouse tracheal contractions,local allergic reactions,and systemic anaphylactic symptoms.PSB-172656 constitutes a unique pharmacological tool and has the potential to be developed as a drug for mast cell-mediated hypersensitivity reactions and chronic inflammatory diseases,addressing a huge unmet medical need.
基金supported by the German Diabetes Association(DDG)(D.T.)the German Research Foundation(DFG)in CRC1423/2(project number 421152132,C04(S.P.)).
文摘In a study published recently in Nature,Sass,Ma,and colleagues describe the neurokinin 2 receptor(NK2R),a G protein-coupled receptor(GPCR),as a novel regulator of food intake as well as energy expenditure,and develop and characterize selective agonists that effectively activate NK2R to promote weight loss.Most interestingly,the authors bridge the gap between rodents and primates,raising hopes for novel treatment options.1 Although obesity cases are continuously rising,thereby contributing to major health problems,long-term effective treatment options are still limited.However,it is well established that GPCRs and their pathways are involved in the regulation of different processes controlling appetite,food intake,or energy homeostasis.Thus,several receptors expressed in neurons governing food intake have been proposed to be promising targets for body weight reduction.However,currently the only GPCR agonists approved for obesity treatment are targeting incretin receptors(receptors for glucagon-like peptide-1(GLP1R),glucose-dependent insulinotropic peptide(GIP),glucagon(GCGR))(Fig.1).
基金supported by the National Institutes of Health Fund (Nos.DK081343,DK090036 and GM104037 to Grace L.Guo)the National Natural Science Foundation of China (No.81302059)+2 种基金the Natural Science Foundation of Heilongjiang Province of China (No.LC2013C35)the Foundation of Educational Committee of Heilongjiang Province of China (No.12541300)supported by the Scientific Research Foundation for the Returned Overseas Chinese Scholars,State Education Ministry and Science Foundation for The Excellent Youth Scholars of the Fourth Hospital of Harbin Medical University in China
文摘The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy(PH) model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids(BAs) are ligands of farnesoid X receptor(FXR), a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potentialuse of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration.
基金This research was supported by the grants from the National Natural Science Foundation of China （No. 30973175）, Scientific Research Foundation for Returning Scholars of Education Ministry of China （No. 0601-18920006）, Scientific and Technological Research Foundation of Shaanxi Province （No. 2007K09-09）, and the Clinical Research Fundation of First Hospital of Xi＇an Jiaotong University of China.
文摘Background OGR1 was found as a G-protein coupled receptor （GPCR） and proton sensor. Our previous studies have found that OGR1 has inhibitory effect on the metastasis of prostate cancer. In order to investigate the roles of OGR1 gene in the biological activities of ovarian cancer, we studied the OGR1 effects on ovarian cancer cells, HEY cells.Methods OGR1 gene was transfected into HEY cell, in which endogenous expression is low. OGR1-overxepressed cells and vector-transfected cells were compared in different assays. Western blotting was employed to confirm the high expression level of OGR1. Cell proliferation was determined by MTT assay and cell doubling time assay. Cell migration assay （transwell assay） and cell adhesion assay were performed to determine the migration and adhesion potential of cells. Student＇s t test was employed for statistical analysis.Results Proliferation of OGR1-overexpressed cells was significantly reduced （P ＜0.01）; cell migration was significantly inhibited in the OGR1-transfected cells （P ＜0.01）; cell adhesion to extracellular matrix including fibronectin, vitronectin,collagen Ⅰ/Ⅳ was significantly increased （P ＜0.01）.Conclusions OGR1 expression in human ovarian cancer cells significantly inhibited the cell proliferation and migration,but significantly enhanced cell adhesion to the extracellular matrix. It indicated that OGR1 may be a tumor suppressor gene for ovarian cancer.
基金supported in part by the National Natural Science Foundation of China(81228021)US National Institutes of Health(DK081654)
文摘Canonical transient receptor potential 4(TRPC4) forms non-selective cation channels that contribute to phospholipase C-dependent Ca2+ entry into cells following stimulation of G protein coupled receptors and receptor tyrosine kinases.Moreover,the channels are regulated by pertussis toxin-sensitive Gi/o proteins,lipids,and various other signaling mechanisms.TRPC4-containing channels participate in the regulation of a variety of physiological functions,including excitability of both gastrointestinal smooth muscles and brain neurons.This review is to present recent advances in the understanding of physiology and development of small molecular modulators of TRPC4 channels.
基金the National Key Research and Development Programs of China(2017YFD0200400 and 2017YFD0201202)the National Natural Science Foundation of China(31501699).
文摘Fungal G-protein coupled receptors(GPCRs)play essential roles in sensing environmental cues including host signals.The study of GPCR in mediating fungus-insect interactions is still limited.Here we report the evolution of GPCR genes encoded in the entomopathogenic Metarhizium species and found the expansion of Pth11-like GPCRs in the generalist species with a wide host range.By deletion of ten candidate genes MrGpr1–MrGpr10 selected from the six obtained subfamilies in the generalist M.robertsii,we found that each of them played a varied level of roles in mediating appressorium formation.In particular,deletion of MrGpr8 resulted in the failure of appressorium formation on different substrates and the loss of virulence during topical infection of insects but not during injection assays when compared with the wild-type(WT)strain.Further analysis revealed that disruption of MrGpr8 substantially impaired the nucleus translocation of the mitogen-activated protein kinase(MAPK)Mero-Fus3 but not the MAPK Mero-Slt2 during appressorium formation.We also found that the defect ofΔMrGpr8 could not be rescued with the addition of cyclic AMP for appressorium formation.Relative to the WT,differential expression of the selected genes have also been detected inΔMrGpr8.The results of this study may benefit the understanding of fungus-interactions mediated by GPCRs.
