Enterovirus D68(EV-D68)and enterovirus A71(EV-A71)are two major types of enteroviruses that pose emerging challenges to public health and have the potential to cause outbreaks,yet their pathogenic mechanisms remain la...Enterovirus D68(EV-D68)and enterovirus A71(EV-A71)are two major types of enteroviruses that pose emerging challenges to public health and have the potential to cause outbreaks,yet their pathogenic mechanisms remain largely unexplored.Arrestin domain containing 3(ARRDC3)is a vital regulator of glucose metabolism,cancer development,and inflammation.Whether ARRDC3 contributes to innate antiviral immunity is undefined.Here,we found that enterovirus infection induces ARRDC3 expression at both the mRNA and protein levels,thereby inhibiting enterovirus replication.Moreover,we demonstrate that the expression of Yes-associated protein(YAP),a key effector of the Hippo pathway,is severely downregulated by ARRDC3 via lysosomal pathway.YAP facilitates enterovirus replication by suppressing the interferon pathway during the later stage of enterovirus infection,independent of its transcriptional activity.Finally,the ARRDC3-YAP pathway exhibits a broad-spectrum antiviral effect in various viral infections,including those caused by human parainfluenza virus type 3(HPIV3)and vesicular stomatitis virus(VSV).Collectively,our results identify the critical role of ARRDC3 and its negative regulatory effect on YAP in the innate antiviral response,suggesting a novel therapeutic strategy against virus infection.展开更多
β-arrestin2是G蛋白偶联受体的负反馈调控蛋白,介导受体的脱敏,此外β-arrestin2还可以通过招募信号分子,介导G蛋白非依赖的信号传导过程。β-arrestin2广泛分布于各重要脑区,参与神经环路的信号传递。本文旨在研究β-arrestin2在可卡...β-arrestin2是G蛋白偶联受体的负反馈调控蛋白,介导受体的脱敏,此外β-arrestin2还可以通过招募信号分子,介导G蛋白非依赖的信号传导过程。β-arrestin2广泛分布于各重要脑区,参与神经环路的信号传递。本文旨在研究β-arrestin2在可卡因诱导的小鼠奖赏行为中的作用。采用β-arrestin2基因敲除小鼠(Arrb2/),检测了β-arrestin2在不同剂量可卡因诱导的条件性位置偏爱(conditioned place preference,CPP)形成中的作用,还检测了其在可卡因诱导的自主活动性变化中的作用。结果显示,在中等剂量(20mg/kg)和高剂量(30mg/kg)可卡因诱导的CPP实验中,Arrb2/小鼠比野生型小鼠(Arrb2+/+)表现出更强的可卡因诱导的位置偏爱,而在低剂量(10mg/kg)可卡因实验中两者无显著性差异。可卡因诱导的Arrb2/小鼠的自主活动性显著低于Arrb2+/+小鼠。以上结果提示,β-arresstin2在可卡因诱导的奖赏行为中起重要作用。展开更多
The purpose of this contribution is to review our current understanding of the source and biochemistry of the circadian efferent input to the eyes of the American horseshoe crab Limuluspolyphemus and the impact of thi...The purpose of this contribution is to review our current understanding of the source and biochemistry of the circadian efferent input to the eyes of the American horseshoe crab Limuluspolyphemus and the impact of this input on the structure, physiology and biochemistry of Limulus eyes. Special emphasis is given to the role of the biogenic amine octopamine and bio- chemical cascades it activates in the eyes. In addition to reviewing published data, we present new data showing that octopamine elevates cAMP levels in Limulus lateral eyes, and we partially characterize the pharmacology of the receptors involved in this response. We also present new data showing that octopamine regulates gene expression in Limulus lateral eyes by activating a cAMP cascade展开更多
BACKGROUND Tobacco-related products,containing the highly addictive nicotine together with numerous other harmful toxicants and carcinogens,have been clearly associated with coronary artery disease,heart failure,strok...BACKGROUND Tobacco-related products,containing the highly addictive nicotine together with numerous other harmful toxicants and carcinogens,have been clearly associated with coronary artery disease,heart failure,stroke,and other heart diseases.Among the mechanisms by which nicotine contributes to heart disease is elevation of the renin-angiotensin-aldosterone system(RAAS)activity.Nicotine,and its major metabolite in humans cotinine,have been reported to induce RAAS activation,resulting in aldosterone elevation in smokers.Aldosterone has various direct and indirect adverse cardiac effects.It is produced by the adrenal cortex in response to angiotensin II(AngII)activating AngII type 1 receptors.RAAS activity increases in chronic smokers,causing raised aldosterone levels(nicotine exposure causes the same in rats).AngII receptors exert their cellular effects via either G proteins or the twoβarrestins(βarrestin1 and-2).AIM Since adrenal?arrestin1 is essential for adrenal aldosterone production and nicotine/cotinine elevate circulating aldosterone levels in humans,we hypothesized that nicotine activates adrenal?arrestin1,which contributes to RAAS activation and heart disease development.METHODS We studied human adrenocortical zona glomerulosa H295R cells and found that nicotine and cotinine upregulateβarrestin1 mRNA and protein levels,thereby enhancing AngII-dependent aldosterone synthesis and secretion.RESULTS In contrast,siRNA-mediatedβarrestin1 knockdown reversed the effects of nicotine on AngII-induced aldosterone production in H295 R cells.Importantly,nicotine promotes hyperaldosteronism via adrenalβarrestin1,thereby precipitating cardiac dysfunction,also in vivo,since nicotine-exposed experimental rats with adrenal-specificβarrestin1 knockdown display lower circulating aldosterone levels and better cardiac function than nicotine-exposed control animals with normal adrenalβarrestin1 expression.CONCLUSION Adrenalβarrestin1 upregulation is one of the mechanisms by which tobacco compounds,like nicotine,promote cardio-toxic hyperaldosteronism in vitro and in vivo.Thus,adrenalβarrestin1 represents a novel therapeutic target for tobaccorelated heart disease prevention or mitigation.展开更多
The activation of the mitogen-activated protein(MAP) kinases extracellular signal-regulated kinase(ERK)1/2 was traditionally used as a readout of signaling of G protein-coupled receptors(GPCRs) via arrestins, as oppos...The activation of the mitogen-activated protein(MAP) kinases extracellular signal-regulated kinase(ERK)1/2 was traditionally used as a readout of signaling of G protein-coupled receptors(GPCRs) via arrestins, as opposed to conventional GPCR signaling via G proteins. Several recent studies using HEK293 cells where all G proteins were genetically ablated or inactivated, or both non-visual arrestins were knocked out, demonstrated that ERK1/2 phosphorylation requires G protein activity, but does not necessarily require the presence of non-visual arrestins. This appears to contradict the prevailing paradigm. Here we discuss these results along with the recent data on gene edited cells and arrestinmediated signaling. We suggest that there is no real controversy. G proteins might be involved in the activation of the upstream-most MAP3Ks, although in vivo most MAP3K activation is independent of heterotrimeric G proteins, being initiated by receptor tyrosine kinases and/or integrins. As far as MAP kinases are concerned, the best-established role of arrestins is scaffolding of the three-tiered cascades(MAP3K-MAP2 K-MAPK). Thus, it seems likely that arrestins, GPCRbound and free, facilitate the propagation of signals in these cascades, whereas signal initiation via MAP3K activation may be independent of arrestins. Different MAP3Ks are activated by various inputs, some of which are mediated by G proteins, particularly in cell culture, where we artificially prevent signaling by receptor tyrosine kinases and integrins, thereby favoring GPCR-induced signaling. Thus, there is no reason to change the paradigm: Arrestins and G proteins play distinct non-overlapping roles in cell signaling.展开更多
In a recent study published in Nature by Chen et al.,six novel cryo-EM structures of atypical chemokine receptor 3(ACKR3)complexes with Arrestin2(Arr2,also known asβ-arrestin1)and Arrestin3(Arr3,also known asβ-arres...In a recent study published in Nature by Chen et al.,six novel cryo-EM structures of atypical chemokine receptor 3(ACKR3)complexes with Arrestin2(Arr2,also known asβ-arrestin1)and Arrestin3(Arr3,also known asβ-arrestin2)were resolved using a novel nanobody,Fab7,which stabilizes active arrestin independent of the isoform,interacting receptor or its phosphorylation pattern.1 This work provides critical insights into G protein-coupled receptor(GPCR)–arrestin interactions under specific GPCR kinase(GRK)phosphorylation conditions,allowing an unprecedented direct comparison of these dynamic signaling complexes.展开更多
A remarkable study by Guo et al.,published in Cell,suggests a compelling new direction for improving pain management:biased allosteric modulation of the neurotensin receptor 1(NTSR1),using the drug-like molecule SBI-8...A remarkable study by Guo et al.,published in Cell,suggests a compelling new direction for improving pain management:biased allosteric modulation of the neurotensin receptor 1(NTSR1),using the drug-like molecule SBI-810,promotesβ-arrestin2(βarr2)recruitment while avoiding canonical G protein signaling–thereby providing robust analgesia across a plethora of rodent models of both acute and chronic pain without impairing motor function,cognition,or causing opioid-like dependency.1,2 SBI-810 is introduced as a highly promising molecule underscoring the therapeutic potential of biased and allosteric G protein-coupled receptor(GPCR)ligands to address an urgent unmet medical need.展开更多
基金supported by the National Natural Science Foundation of China(31600139)the Chongqing Science and Technology Bureau(cstc2016jcyjA0020+3 种基金CSTB2024NSCQ-KJFZMSX0067)the Yuzhong District Science and Technology Commission(20190123)the Chongqing Municipal Education Commission(KJQN202300415)the Project of Undergraduates Innovating Experiment,and the Project of Tutorial System of Excellent Medical Undergraduates in the Lab Teaching and Management Center of Chongqing Medical University(S202410631068,LTMCMTS202458,LTMCMTS202459,LTMCMTS202460 and LTMCMTS202461).
文摘Enterovirus D68(EV-D68)and enterovirus A71(EV-A71)are two major types of enteroviruses that pose emerging challenges to public health and have the potential to cause outbreaks,yet their pathogenic mechanisms remain largely unexplored.Arrestin domain containing 3(ARRDC3)is a vital regulator of glucose metabolism,cancer development,and inflammation.Whether ARRDC3 contributes to innate antiviral immunity is undefined.Here,we found that enterovirus infection induces ARRDC3 expression at both the mRNA and protein levels,thereby inhibiting enterovirus replication.Moreover,we demonstrate that the expression of Yes-associated protein(YAP),a key effector of the Hippo pathway,is severely downregulated by ARRDC3 via lysosomal pathway.YAP facilitates enterovirus replication by suppressing the interferon pathway during the later stage of enterovirus infection,independent of its transcriptional activity.Finally,the ARRDC3-YAP pathway exhibits a broad-spectrum antiviral effect in various viral infections,including those caused by human parainfluenza virus type 3(HPIV3)and vesicular stomatitis virus(VSV).Collectively,our results identify the critical role of ARRDC3 and its negative regulatory effect on YAP in the innate antiviral response,suggesting a novel therapeutic strategy against virus infection.
基金supported by National Natural Science Foundation of China(No.30901798)the Science and Technology Program of Shanghai Science and Technology CommissionChina(No.12JC1401000)
文摘β-arrestin2是G蛋白偶联受体的负反馈调控蛋白,介导受体的脱敏,此外β-arrestin2还可以通过招募信号分子,介导G蛋白非依赖的信号传导过程。β-arrestin2广泛分布于各重要脑区,参与神经环路的信号传递。本文旨在研究β-arrestin2在可卡因诱导的小鼠奖赏行为中的作用。采用β-arrestin2基因敲除小鼠(Arrb2/),检测了β-arrestin2在不同剂量可卡因诱导的条件性位置偏爱(conditioned place preference,CPP)形成中的作用,还检测了其在可卡因诱导的自主活动性变化中的作用。结果显示,在中等剂量(20mg/kg)和高剂量(30mg/kg)可卡因诱导的CPP实验中,Arrb2/小鼠比野生型小鼠(Arrb2+/+)表现出更强的可卡因诱导的位置偏爱,而在低剂量(10mg/kg)可卡因实验中两者无显著性差异。可卡因诱导的Arrb2/小鼠的自主活动性显著低于Arrb2+/+小鼠。以上结果提示,β-arresstin2在可卡因诱导的奖赏行为中起重要作用。
基金supported by grants from the National Science Foundation (NSF)the Whitehall Foundation and the Whimey Laboratory
文摘The purpose of this contribution is to review our current understanding of the source and biochemistry of the circadian efferent input to the eyes of the American horseshoe crab Limuluspolyphemus and the impact of this input on the structure, physiology and biochemistry of Limulus eyes. Special emphasis is given to the role of the biogenic amine octopamine and bio- chemical cascades it activates in the eyes. In addition to reviewing published data, we present new data showing that octopamine elevates cAMP levels in Limulus lateral eyes, and we partially characterize the pharmacology of the receptors involved in this response. We also present new data showing that octopamine regulates gene expression in Limulus lateral eyes by activating a cAMP cascade
基金Supported by a Nova Southeastern University’s President’s Faculty Research and Development Grant award,No.335467American Foundation for Pharmaceutical Research Gateway to Research Grant No.2017-333325(both to Lymperopoulos A)。
文摘BACKGROUND Tobacco-related products,containing the highly addictive nicotine together with numerous other harmful toxicants and carcinogens,have been clearly associated with coronary artery disease,heart failure,stroke,and other heart diseases.Among the mechanisms by which nicotine contributes to heart disease is elevation of the renin-angiotensin-aldosterone system(RAAS)activity.Nicotine,and its major metabolite in humans cotinine,have been reported to induce RAAS activation,resulting in aldosterone elevation in smokers.Aldosterone has various direct and indirect adverse cardiac effects.It is produced by the adrenal cortex in response to angiotensin II(AngII)activating AngII type 1 receptors.RAAS activity increases in chronic smokers,causing raised aldosterone levels(nicotine exposure causes the same in rats).AngII receptors exert their cellular effects via either G proteins or the twoβarrestins(βarrestin1 and-2).AIM Since adrenal?arrestin1 is essential for adrenal aldosterone production and nicotine/cotinine elevate circulating aldosterone levels in humans,we hypothesized that nicotine activates adrenal?arrestin1,which contributes to RAAS activation and heart disease development.METHODS We studied human adrenocortical zona glomerulosa H295R cells and found that nicotine and cotinine upregulateβarrestin1 mRNA and protein levels,thereby enhancing AngII-dependent aldosterone synthesis and secretion.RESULTS In contrast,siRNA-mediatedβarrestin1 knockdown reversed the effects of nicotine on AngII-induced aldosterone production in H295 R cells.Importantly,nicotine promotes hyperaldosteronism via adrenalβarrestin1,thereby precipitating cardiac dysfunction,also in vivo,since nicotine-exposed experimental rats with adrenal-specificβarrestin1 knockdown display lower circulating aldosterone levels and better cardiac function than nicotine-exposed control animals with normal adrenalβarrestin1 expression.CONCLUSION Adrenalβarrestin1 upregulation is one of the mechanisms by which tobacco compounds,like nicotine,promote cardio-toxic hyperaldosteronism in vitro and in vivo.Thus,adrenalβarrestin1 represents a novel therapeutic target for tobaccorelated heart disease prevention or mitigation.
基金Supported by National Institutes of Health RO1 grants,No.EY011500National Institutes of Health R35 grants,No.GM122491Cornelius Vanderbilt Endowed Chair(Vanderbilt University),No.NS065868(to Gurevich VV)and No.DA030103(to Gurevich EV)
文摘The activation of the mitogen-activated protein(MAP) kinases extracellular signal-regulated kinase(ERK)1/2 was traditionally used as a readout of signaling of G protein-coupled receptors(GPCRs) via arrestins, as opposed to conventional GPCR signaling via G proteins. Several recent studies using HEK293 cells where all G proteins were genetically ablated or inactivated, or both non-visual arrestins were knocked out, demonstrated that ERK1/2 phosphorylation requires G protein activity, but does not necessarily require the presence of non-visual arrestins. This appears to contradict the prevailing paradigm. Here we discuss these results along with the recent data on gene edited cells and arrestinmediated signaling. We suggest that there is no real controversy. G proteins might be involved in the activation of the upstream-most MAP3Ks, although in vivo most MAP3K activation is independent of heterotrimeric G proteins, being initiated by receptor tyrosine kinases and/or integrins. As far as MAP kinases are concerned, the best-established role of arrestins is scaffolding of the three-tiered cascades(MAP3K-MAP2 K-MAPK). Thus, it seems likely that arrestins, GPCRbound and free, facilitate the propagation of signals in these cascades, whereas signal initiation via MAP3K activation may be independent of arrestins. Different MAP3Ks are activated by various inputs, some of which are mediated by G proteins, particularly in cell culture, where we artificially prevent signaling by receptor tyrosine kinases and integrins, thereby favoring GPCR-induced signaling. Thus, there is no reason to change the paradigm: Arrestins and G proteins play distinct non-overlapping roles in cell signaling.
文摘In a recent study published in Nature by Chen et al.,six novel cryo-EM structures of atypical chemokine receptor 3(ACKR3)complexes with Arrestin2(Arr2,also known asβ-arrestin1)and Arrestin3(Arr3,also known asβ-arrestin2)were resolved using a novel nanobody,Fab7,which stabilizes active arrestin independent of the isoform,interacting receptor or its phosphorylation pattern.1 This work provides critical insights into G protein-coupled receptor(GPCR)–arrestin interactions under specific GPCR kinase(GRK)phosphorylation conditions,allowing an unprecedented direct comparison of these dynamic signaling complexes.
基金funding by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)under DFG DE 1546/12-1(M.D.),559839626(M.D.),and 538291523(S.A.M.S.)funding from Ghent University BOF program grant number BOF23/PDO/073funding enabled and organized by Projekt DEAL.
文摘A remarkable study by Guo et al.,published in Cell,suggests a compelling new direction for improving pain management:biased allosteric modulation of the neurotensin receptor 1(NTSR1),using the drug-like molecule SBI-810,promotesβ-arrestin2(βarr2)recruitment while avoiding canonical G protein signaling–thereby providing robust analgesia across a plethora of rodent models of both acute and chronic pain without impairing motor function,cognition,or causing opioid-like dependency.1,2 SBI-810 is introduced as a highly promising molecule underscoring the therapeutic potential of biased and allosteric G protein-coupled receptor(GPCR)ligands to address an urgent unmet medical need.
