G protein-coupled receptor 37(GPR37) emerges as an important modulator of adenosinergic transmission in the striatum

G protein-coupled receptor 37 (GPR37), also known as parkin associated endothelin-like (Pael) receptor, is an orphan G protein- coupled receptor, which suffers a defective parking ubiquitination in autosomal recessive Parkinson’s disease promoting its endoplasmic reticulum aggregation and stress, neurotoxicity and neuronal death (Takahashi and Imai, 2003). Interestingly, we have demonstrated previously that GPR37 heteromerizes with adenosine A2A receptor (A2AR) in the striatum (Morato et al., 2017;Sokolina et al., 2017).

Immunomodulation of Proton-activated G Protein-coupled Receptors in Inflammation

Proton-activated G protein-coupled receptors(GPCRs),initially discovered by Ludwig in 2003,are widely distributed in various tissues.These receptors have been found to modulate the immune system in several inflammatory diseases,including inflammatory bowel disease,atopic dermatitis,and asthma.Proton-activated GPCRs belong to the G protein-coupled receptor family and can detect alternations in extracellular pH.This detection triggers downstream signaling pathways within the cells,ultimately influencing the function of immune cells.In this review,we specifically focused on investigating the immune response of proton-activated GPCRs under inflammatory conditions.

G protein-coupled estrogen receptor in colon function, immune regulation and carcinogenesis

Estrogens play important roles in the development and progression of multiple tumor types.Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as the breast,endometrium and ovary,but also in the development of colorectal cancer(CRC).The effects of estrogens in physiological and pathophysiological conditions are mediated by the nuclear estrogen receptorsαandβ,as well as the membranebound G protein-coupled estrogen receptor(GPER).The roles of GPER in CRC development and progression,however,remain poorly understood.Studies on the functions of GPER in the colon have shown that this estrogen receptor regulates colonic motility as well as immune responses in CRC-associated diseases,such as Crohn’s disease and ulcerative colitis.GPER is also involved in cell cycle regulation,endoplasmic reticulum stress,proliferation,apoptosis,vascularization,cell migration,and the regulation of fatty acid and estrogen metabolism in CRC cells.Thus,multiple lines of evidence suggest that GPER may play an important role in colorectal carcinogenesis.In this review,we present the current state of knowledge regarding the contribution of GPER to colon function and CRC.

Roles of G protein-coupled receptors in inflammatory bowel disease

Inflammatory bowel disease(IBD)is a complex disease with multiple pathogenic factors.Although the pathogenesis of IBD is still unclear,a current hypothesis suggests that genetic susceptibility,environmental factors,a dysfunctional immune system,the microbiome,and the interactions of these factors substantially contribute to the occurrence and development of IBD.Although existing and emerging drugs have been proven to be effective in treating IBD,none can cure IBD permanently.G protein-coupled receptors(GPCRs)are critical signaling molecules implicated in the immune response,cell proliferation,inflammation regulation and intestinal barrier maintenance.Breakthroughs in the understanding of the structures and functions of GPCRs have provided a driving force for exploring the roles of GPCRs in the pathogenesis of diseases,thereby leading to the development of GPCR-targeted medication.To date,a number of GPCRs have been shown to be associated with IBD,significantly advancing the drug discovery process for IBD.The associations between GPCRs and disease activity,disease severity,and disease phenotypes have also paved new avenues for the precise management of patients with IBD.In this review,we mainly focus on the roles of the most studied proton-sensing GPCRs,cannabinoid receptors,and estrogen-related GPCRs in the pathogenesis of IBD and their potential clinical values in IBD and some other diseases.

Adrenal G protein-coupled receptor kinase-2 in regulation of sympathetic nervous system activity in heart failure

Heart failure(HF), the number one cause of death in the western world, is caused by the insufficient performance of the heart leading to tissue underperfusion in response to an injury or insult. It comprises complex interactions between important neurohormonal mechanisms that try but ultimately fail to sustain cardiac output. The most prominent such mechanism is the sympathetic(adrenergic) nervous system(SNS), whose activity and outflow are greatly elevated in HF. SNS hyperactivity confers significant toxicity to the failing heart and markedly increases HF morbidity and mortality via excessive activation of adrenergic receptors, which are G protein-coupled receptors. Thus, ligand binding induces their coupling to heterotrimeric G proteins that transduce intracellular signals. G protein signaling is turned-off by the agonist-bound receptor phosphorylation courtesy of G protein-coupled receptor kinases(GRKs), followed by βarrestin binding, which prevents the GRK-phosphorylated receptor from further interaction with the G proteins and simultaneously leads it inside the cell(receptor sequestration). Recent evidence indicates that adrenal GRK2 and βarrestins can regulate adrenal catecholamine secretion, thereby modulating SNS activity in HF. The present review gives an account of all these studies on adrenal GRKs and βarrestins in HF and discusses the exciting new therapeutic possibilities for chronic HF offered by targeting these proteins pharmacologically.

Takeda G protein-coupled receptor 5 modu⁃lates depression-like behaviors via hippocam⁃pal CA3 pyramidal neurons afferent to dorso⁃lateral septum

OBJECTIVE Takeda G protein-coupled receptor 5(TGR5)is recognized as a promising target for type 2 diabetes and metabolic syndrome;its expression has been demonstrat⁃ed in the brain and is thought to be neuroprotec⁃tive.Here,we hypothesize that dysfunction of central TGR5 may contribute to the pathogene⁃sis of depression.METHODS In well-established chronic social defeat stress(CSDS)and chronic restraint stress(CRS)models of depression,we investigated the functional roles of TGR5 in CA3 pyramidal neurons(PyNs)and underlying mech⁃anisms of the neuronal circuit in depression(for in vivo studies,n=10;for in vitro studies,n=5-10)using fiber photometry;optogenetic,chemoge⁃netic,pharmacological,and molecular profiling techniques;and behavioral tests.RESULTS Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs.Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777,a specific agonist,protected against CSDS and CRS,exerting sig⁃nificant antidepressant-like effects that were mediated via CA3 PyN activation.Conversely,genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behav⁃iors.Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in Tgr5 knockout mice exposed to CSDS or CRS.Silencing and stimula⁃tion of CA3 PyNs→somatostatin-GABAergic(gamma-aminobutyric acidergic)neurons of the dorsolateral septum circuit bidirectionally regulat⁃ed depression-like behaviors,and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs.CON⁃CLUSION TGR5 can regulate depression via CA3 PyNs→somatostatin-GABAergic neurons of dorsolateral septum transmission,suggesting that TGR5 could be a novel target for developing antidepressants.

Leucine-rich repeat-containing G protein-coupled receptor 5 marks different cancer stem cell compartments in human Caco-2 and LoVo colon cancer lines

BACKGROUND Colon cancer cell lines are widely used for research and for the screening of drugs that specifically target the stem cell compartment of colon cancers.It was reported that colon cancer carcinoma specimens contain a subset of leucine-rich repeatcontaining G protein-coupled receptor 5(LGR5)-expressing stem cells,these socalled“tumour-initiating”cells,reminiscent in their properties of the normal intestinal stem cells(ISCs),may explain the apparent heterogeneity of colon cancer cell lines.Also,colon cancer is initiated by aberrant Wnt signaling in ISCs known to express high levels of LGR5.Furthermore,in vivo reports demonstrate the clonal expansion of intestinal adenomas from a single LGR5-expressing cell.AIM To investigate whether colon cancer cell lines contain cancer stem cells and to characterize these putative cancer stem cells.METHODS A portable fluorescent reporter construct based on a conserved fragment of the LGR5 promoter was used to isolate the cell compartments expressing different levels of LGR5 in two widely used colon cancer cell lines(Caco-2 and LoVo).These cells were then characterized according to their proliferation capacity,gene expression signatures of ISC markers,and their tumorigenic properties in vivo and in vitro.RESULTS The data revealed that the LGR5 reporter can be used to identify and isolate a classical intestinal crypt stem cell-like population from the Caco-2,but not from the LoVo,cell lines,in which the cancer stem cell population is more akin to B lymphoma Moloney murine leukemia virus insertion region 1 homolog(+4 crypt)stem cells.This sub-population within Caco-2 cells exhibits an intestinal cancer stem cell gene expression signature and can both self-renew and generate differentiated LGR5 negative progeny.Our data also show that cells expressing high levels of LGR5/enhanced yellow fluorescent protein(EYFP)from this cell line exhibit tumorigenic-like properties in vivo and in vitro.In contrast,cell compartments of LoVo that are expressing high levels of LGR5/EYFP did not show these stem cell-like properties.Thus,cells that exhibit high levels of LGR5/EYFP expression represent the cancer stem cell compartment of Caco-2 colon cancer cells,but not LoVo cells.CONCLUSION Our findings highlight the presence of a spectrum of different ISC-like compartments in different colon cancer cell lines.Their existence is an important consideration for their screening applications and should be taken into account when interpreting drug screening data.We have generated a portable LGR5-reporter that serves as a valuable tool for the identification and isolation of different colon cancer stem cell populations in colon cancer lines.

G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment

Nonalcoholic fatty liver disease(NAFLD)is a broad-spectrum disease,ranging from simple hepatic steatosis to nonalcoholic steatohepatitis,which can progress to cirrhosis and liver cancer.Abnormal hepatic lipid accumulation is the major manifestation of this disease,and lipotoxicity promotes NAFLD progression.In addition,intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins,resulting in progression of NAFLD to fibrosis and even cirrhosis.G protein-coupled receptors(GPCRs)have been shown to play essential roles in metabolic disorders,such as NAFLD and obesity,through their function as receptors for bile acids and free fatty acids.In addition,GPCRs link gut microbiota-mediated connections in a variety of diseases,such as intestinal diseases,hepatic steatosis,diabetes,and cardiovascular diseases.The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids.GPCR agonists,including peptides and natural products like docosahexaenoic acid,have been applied to investigate their role in liver diseases.Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome.This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment.Overall,understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.

Overexpression of G protein-coupled receptor 31 as a poor prognosticator in human colorectal cancer

AIM To investigate the expression of G protein-coupled receptor 31 (GPR31) and its clinical significance in human colorectal cancer (CRC).METHODS To determine the association between the GPR31 expression and the prognosis of patients, we obtained paraffin-embedded pathological specimens from 466 CRC patients who underwent initial resection. A total of 321 patients from the First Affiliated Hospital of Sun Yat-sen University from January 1996 to December 2008 were included as a training cohort, whereas 145 patients from the Sixth Affiliated Hospital of Sun Yat-sen University from January 2007 to November 2008 were included as a validation cohort. We examined GPR31 expression levels in CRC tissues from two independent cohorts via immunohistochemical staining. All patients were categorized into either a GPR31 low expression group or a GPR31 high expression group. The clinicopathological factors and the prognosis of patients in the GPR31 low expression group and GPR31 high expression group were compared.RESULTS We compared the clinicopathological factors and the prognosis of patients in the GPR31 low expression group and GPR31 high expression group. Significant differences were observed in the number of patients in pM classification between patients in the GPR31 low expression group and GPR31 high expression group (P = 0.007). The five-year survival and tumor-free survival rates of patients were 84.3% and 82.2% in the GPR31 low expression group, respectively, and both rates were 59.7% in the GPR31 high expression group (P < 0.05). Results of the Cox proportional hazard regression model revealed that GPR31 upregulation was associated with shorter overall survival and tumor-free survival of patients with CRC (P < 0.05). Multivariate analysis identified GPR31 expression in colorectal cancer as an independent predictive factor of CRC patient survival (P < 0.05).CONCLUSION High GPR31 expression levels were found to be correlated with pM classification of CRC and to serve as an independent predictive factor of poor survival of CRC patients.

Functionally diverse ligands modulate different activation states of the formyl peptide receptor 2,a G protein-coupled receptor

OBJECTIVE To identify the mechanisms by which the formyl peptide receptor 2(FPR2)mediates both inflammatory and anti-inflammatory signaling in an agonist-dependent manner.METHODS Cells expressing FPR2 were incubated with weak agonists,Aβ42 and Ac2-26,before stimulation with a strong agonist,WKYMVm.Calcium mobilization,c AMP inhibition and MAP kinase activation were measured.Intramolecular FRET were determined using FPR2 constructs with an ECFP attached to the C-terminus and a Fl As H binding motif embedded in the first or third intracellular loop(IL1 or IL3,respectively).RESULTS Aβ42 did not induce significant Ca^(2+) mobilization,but positively modulated WKYMVm-induced Ca^(2+) mobilization and c AMP reduction in a dose-variable manner within a narrow range of ligand concentrations.Treating FPR2-expressing cells with Ac2-26,a peptide with anti-inflammatory activity,negatively modulated WKYMVm-induced Ca^(2+) mobilization and c AMP reduction.Intramolecular FRET assay showed that stimulation of the receptor constructs with Aβ42 brought the C-terminal domain closer to IL1 but away from IL3.An opposite conformational change was induced by Ac2-26.The FPR2 conformation induced by Aβ42 corresponded to enhanced ERK phosphorylation and attenuated p38 MAPK phosphorylation,whereas Ac2-26 induced FPR2 conformational change corresponding to elevated p38 MAPK phosphorylation and reduced ERK phosphorylation.CONCLUSION Aβ42 and Ac2-26 induce different conformational changes in FPR2.These findings provide a structural basis for FPR2 mediation of inflammatory vs anti-inflammatory functions and identify a type of receptor modulation that differs from the classic positive and negative allosteric modulation.

人工智能加速GPCR配体的发现

G protein-coupled receptors(GPCRs)are crucial players in various physiological processes,making them attractive candidates for drug discovery.However,traditional approaches to GPCR ligand discovery are time-consuming and resource-intensive.The emergence of artificial intelligence(AI)methods has revolutionized the field of GPCR ligand discovery and has provided valuable tools for accelerating the identification and optimization of GPCR ligands.In this study,we provide guidelines for effectively utilizing AI methods for GPCR ligand discovery,including data collation and representation,model selection,and specific applications.First,the online resources that are instrumental in GPCR ligand discovery were summarized,including databases and repositories that contain valuable GPCR-related information and ligand data.Next,GPCR and ligand representation schemes that can convert data into computer-readable formats were introduced.Subsequently,the key applications of AI methods in the different stages of GPCR drug discovery were discussed,ranging from GPCR function prediction to ligand design and agonist identification.Furthermore,an AI-driven multi-omics integration strategy for GPCR ligand discovery that combines information from various omics disciplines was proposed.Finally,the challenges and future directions of the application of AI in GPCR research were deliberated.In conclusion,continued advancements in AI techniques coupled with interdisciplina ry collaborations will offer great potential for improving the efficiency of GPCR ligand discovery.

Allosteric modulation of G protein-coupled receptors as a novel therapeutic strategy in neuropathic pain

Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice.Unfortunately,current pharmacological treatments for neuropathic pain lack clinical efficacy and often lead to harmful adverse reactions.As G protein-coupled receptors(GPCRs)are widely distributed throughout the body,including the pain transmission pathway and descending inhibition pathway,the development of novel neuropathic pain treatments based on GPCRs allosteric modulation theory is gaining momentum.Extensive research has shown that allosteric modulators targeting GPCRs on the pain pathway can effectively alleviate symptoms of neuropathic pain while reducing or eliminating adverse effects.This review aims to provide a comprehensive summary of the progress made in GPCRs allosteric modulators in the treatment of neuropathic pain,and discuss the potential benefits and adverse factors of this treatment.We will also concentrate on the development of biased agonists of GPCRs,and based on important examples of biased agonist development in recent years,we will describe universal strategies for designing structure-based biased agonists.It is foreseeable that,with the continuous improvement of GPCRs allosteric modulation and biased agonist theory,effective GPCRs allosteric drugs will eventually be available for the treatment of neuropathic pain with acceptable safety.

Milk fat globule membrane supplementation protects againstβ-lactoglobul-ininduced food allergy in mice via upregulation of regulatory T cells and enhancement of intestinal barrier in a microbiota-derived short-chain fatty acids manner

Milk fat globule membrane(MFGM),which contains abundant glycoproteins and phospholipids,exerts beneficial effects on intestinal health and immunomodulation.The aim of this study was to evaluate the protective effects and possible underlying mechanisms of MFGM on cow’s milk allergy(CMA)in aβ-lactoglobulin(BLG)-induced allergic mice model.MFGM was supplemented to allergic mice induced by BLG at a dose of 400 mg/kg body weight.Results demonstrated that MFGM alleviated food allergy symptoms,decreased serum levels of lipopolysaccharide,pro-inflammatory cytokines,immunoglobulin(Ig)E,Ig G1,and Th2 cytokines including interleukin(IL)-4,while increased serum levels of Th1 cytokines including interferon-γand regulatory T cells(Tregs)cytokines including IL-10 and transforming growth factor-β.MFGM modulated gut microbiota and enhanced intestinal barrier of BLG-allergic mice,as evidenced by decreased relative abundance of Desulfobacterota,Rikenellaceae,Lachnospiraceae,and Desulfovibrionaceae,while increased relative abundance of Bacteroidetes,Lactobacillaceae and Muribaculaceae,and enhanced expressions of tight junction proteins including Occludin,Claudin-1 and zonula occludens-1.Furthermore,MFGM increased fecal short-chain fatty acids(SCFAs)levels,which elevated G protein-coupled receptor(GPR)43 and GPR109A expressions.The increased expressions of GPR43 and GPR109A induced CD103+dendritic cells accumulation and promoted Tregs differentiation in mesenteric lymph node to a certain extent.In summary,MFGM alleviated CMA in a BLG-induced allergic mice model through enhancing intestinal barrier and promoting Tregs differentiation,which may be correlated with SCFAs-mediated activation of GPRs.These findings suggest that MFGM may be useful as a promising functional ingredient against CMA.

The Role of GPER in Sepsis-Induced Myocardial Cell Damage and 28-Day Mortality Risk

Purpose: The role of GPER in sepsis-induced myocardial cell injury and its potential impact on the risk of death within 28 days in sepsis. Methods: An in vitro experiment was conducted to establish a sepsis-induced myocardial cell model. H9C2 myocardial cells were treated with 10 μg/ml lipopolysaccharide (LPS) for 24 hours. The effects of different concentrations of the GPER agonist G1 (1, 3, and 10 μmol/L) on cell viability, expression of inflammatory markers, cell apoptosis, and the NF-κB pathway were evaluated. A Mendelian randomization analysis was conducted using Single Nucleotide Polymorphism (SNPs) related to the GPER gene as instrumental variables to investigate the causal relationship between the GPER gene variations and sepsis (28-day death). Results: The results indicate that the group treated with LPS showed a significant decrease in myocardial cell viability, an increase in concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), higher apoptosis rates, and increased phosphorylation levels of NF-κB p65 (p-P65/P65) and IκB-α (p-IκB-α/IκB-α) compared to the control group (P κB pathway. However, genetic evidence did not show a causal relationship between GPER gene variations and sepsis (28-day death) (P κB pathway. However, genetic evidence did not show a causal relationship between GPER gene variations and sepsis (28-day death).

GPR37在骨髓瘤细胞黏附介导的耐药中的作用及意义

目的:研究G蛋白耦联受体37(orphan G protein-coupled receptor 37,GPR37)在细胞黏附介导的多发性骨髓瘤细胞耐药过程中的表达变化及其生物学作用。方法:采用多发性骨髓瘤细胞株RPMI 8226与纤黏蛋白(fibronectin,FN)或骨髓基质细胞株HS-5共培养构建细胞黏附模型。Western Blot检测GPR37分别在悬浮和黏附状态的RPMI 8226细胞中的蛋白表达水平。钙黄绿素实验检测改变GPR37的表达对RPMI 8226细胞黏附的影响,并采用化疗药物多柔比星处理细胞,CCK-8试剂盒检测上述处理对RPMI 8226细胞活力的影响。结果:Western Blot结果显示GPR37在RPMI8226细胞黏附模型中低表达。钙黄绿素实验结果显示RPMI 8226细胞过表达GPR37后其黏附能力显著降低。CCK-8实验结果表明GPR37过表达能显著增强RPMI 8226细胞对化疗药物多柔比星的敏感性。结论:GPR37可能通过影响骨髓瘤细胞与基质细胞的黏附能力从而影响其对化疗药物的敏感性。

G蛋白偶联受体37(GPR37)上调促进人胶质瘤U251细胞的增殖

目的探讨G蛋白偶联受体37(GPR37)表达上调对人胶质瘤U251细胞增殖的影响。方法构建携带GPR37基因的重组质粒,采用脂质体转染法在U251细胞上调表达GPR37,采用实时荧光定量PCR检测GPR37 mRNA水平,Western blot法检测GPR37、磷酸化的蛋白激酶B[p-AKT(Ser473)]蛋白水平,CCK-8法检测U251细胞增殖情况,流式细胞术检测U251细胞的细胞周期。结果与阴性对照组相比,过表达GPR37组细胞的GPR37 mRNA和蛋白水平显著提高。上调细胞的GPR37水平后,明显增加U251细胞的增殖、G1/G0期细胞比例降低,S期和G2期细胞比例升高,并增加p-AKT(Ser473)蛋白水平。结论上调U251细胞的GPR37水平可加速U251细胞周期进程、活化AKT途径并促进细胞增殖。

Phosphorylation of group I metabotropic glutamate receptors in drug addiction and translational research

Protein phosphorylation is an important posttranslational modification of group I metabotropic glutamate receptors （ mGluR1 and mGluR5 subtypes, mGluR1/5 ） which are widely distributed throughout the mammalian brain. Several common protein kinases are involved in this type of modification, including protein kinase A, protein kinase C, and extracellular signal-regulated kinase. Through constitutive and activity-dependent phosphorylation of mGluR1/5 at specific residues, protein kinases regulate trafficking, subcellular/subsynaptic distribution, and function of modified receptors. Increasing evidence demonstrates that mGluR1/5 phosphorylation in the mesolimbic reward circuitry is sensitive to chronic psychostimulant exposure and undergoes adaptive changes in its abundance and activity. These changes contribute to long-term excitatory synaptic plasticity related to the addictive property of drugs of abuse. The rapid progress in uncovering the neurochemical basis of addiction has fostered bench-to-bed translational research by targeting mGluR1/5 for developing effective pharmacotherapies for treating addiction in humans. This review summarizes recent data from the studies analyzing mGluR1/5 phosphorylation. Phosphorylation-dependent mechanisms in stimulant-in-duced mGluR1/5 and behavioral plasticity are also discussed in association with increasing interest in mGluR1/5 in translational medicine.

GPR37在肺腺癌中的表达及其临床意义

目的探讨G蛋白偶联受体37(GPR37)基因在肺腺癌中的表达情况及其临床意义。方法从癌症基因组图谱(TCGA)数据库下载510例肺腺癌组织(肿瘤组)RNA序列及对应的患者临床数据,其中包括56例癌旁组织(癌旁对照组)的相关数据,对GPR37的表达与肺腺癌临床病理特征的相关性进行分析比较。结果肿瘤组的GPR37的表达水平高于癌旁对照组,差异有统计学意义(P<0.05)。单因素COX逻辑回归分析显示,GPR37的表达水平与性别、年龄以及M分期无关,差异无统计学意义(P>0.05),与T分期及N分期有关,差异有统计学意义(P<0.05)。生存预后分析结果显示,GPR37表达水平与肺腺癌患者预后有显著相关性,差异有统计学意义(P<0.05),表达越高,预后越差。多因素COX风险比例模型结果显示,高GPR37表达水平、Stage分期是肺腺癌患者预后差的独立危险因素。结论依据GPR37在肺腺癌中高表达,推测其在肺腺癌的发生发展过程中可能发挥了一定的作用,从而影响了肺腺癌患者的预后。因此,GPR37可作为肺腺癌潜在治疗靶点或诊断标志物。

G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes

Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide.Fat accumulation“sensitizes”the liver to insult and leads to nonalcoholic steatohepatitis(NASH).G protein-coupled receptor 35(GPR35)is involved in metabolic stresses,but its role in NAFLD is unknown.We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis.Specifically,we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose(HFCF)diet-induced steatohepatitis,whereas loss of GPR35 had the opposite effect.Administration of the GPR35 agonist kynurenic acid(Kyna)suppressed HFCF diet-induced steatohepatitis in mice.Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4(STARD4)through the ERK1/2 signaling pathway,ultimately resulting in hepatic cholesterol esterification and bile acid synthesis(BAS).The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1(CYP7A1)and CYP8B1,promoting the conversion of cholesterol to bile acid.The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice.STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice.Our findings indicate that the GPR35–STARD4 axis is a promising therapeutic target for NAFLD.

GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone

BACKGROUND In the heart,aldosterone(Aldo)binds the mineralocorticoid receptor(MR)to exert damaging,adverse remodeling-promoting effects.We recently showed that G protein-coupled receptor-kinase(GRK)-5 blocks the cardiac MR by directly phosphorylating it,thereby repressing its transcriptional activity.MR antagonist(MRA)drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure.Non-steroidal MRAs,such as finerenone,may provide better cardio-protection against Aldo than classic,steroidal MRAs,like spironolactone and eplerenone.AIM To investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade.METHODS We used H9c2 cardiomyocytes,which endogenously express the MR and GRK5.RESULTS GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone.Unlike eplerenone,finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity,thus displaying inverse agonism.GRK5 is necessary for finerenone’s inverse agonism,since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity.Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels.Finally,GRK5 is necessary for the antiapoptotic,anti-oxidative,and anti-fibrotic effects of both finerenone and eplerenone against Aldo,as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis,oxidative stress,and fibrosis.CONCLUSION Finerenone,but not eplerenone,induces GRK5-dependent cardiac MR inhibition,which underlies,at least in part,its higher potency and efficacy,compared to eplerenone,as an MRA in the heart.GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.