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Increased excitatory amino acid transporter 2 levels in basolateral amygdala astrocytes mediate chronic stress–induced anxiety-like behavior

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Neural Regeneration Research 2025年第6期20卷 1721-1734页

作者： Xirong Xu Shoumin Xuan Shuai Chen Dan Liu Qian Xiao Jie Tu Shenzhen Key Laboratory of Neuroimmunomodulation for Neurological Diseases Shenzhen-Hong Kong Institute of Brain ScienceShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong ProvinceChina CAS Key Laboratory of Brain Connectome and Manipulation Brain Cognition and Brain Disease Institute(BCBDI)Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong ProvinceChina Guangdong Provincial Key Laboratory of Brain Connectome and Behavior the Brain Cognition and Brain Disease Institute(BCBDI)Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong ProvinceChina University of Chinese of Academy of Sciences BeijingChina Faculty of Life and Health Sciences Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong ProvinceChina

The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with ***, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal *** knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was ob

关键词： anxiety astrocytes basolateral amygdala behavior dihydrokainic acid excitatory amino acid transporter 2 fiber photometry glutamate LDN-212320 transporter

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Crystal structure of a bacterial homolog to human lysosomal transporter,spinster

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Science Bulletin 2019年第18期64卷 1310-1317页

作者： Fu Zhoua Deqiang Yao Bing Rao Li Zhang Wang Nie Yan Zou Jie Zhao Yu Cao CAS Center for Excellence on Molecular Cell Science Institute of Biochemistry and Cell BiologyChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 201210China Institute of Precision Medicine The Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai 200125China School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China Department of Orthopaedics Shanghai Key Laboratory of Orthopaedic ImplantShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China

Lysosomes break down various biomolecules and spinster is one of the major efflux carriers removing degradation products from lysosomal lumen to keep it in healthy size and proper *** it is well established that a dysfunctional spinster will cause enlarged lysosomes and in turn lead to developmental defects and abnormal behavior in animals,little was known about the transportation mechanism and substrate specificity of ***,we report a crystal structure of spinster homolog from Hyphomonas neptunium,HnSPNS,in its inward-facing conformation with and without substrate *** is crystallized in a monomer and a substrate-binding cavity was formed in the center of its transmembrane helices.A blob of electron density corresponding to its substrate was found in the cavity near a conserved residue,R42,which is locked in position by the interactions with conserved residues E129 and *** results suggest that human spinster serves as a transporter translocating negativelycharged lipophilic small molecules and E129 might serve as a switch to control the conformational change via its protonation-deprotonation cycle.

关键词： Major facilitator superfamily transporter Spinster Membrane protein

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Insulin-like growth factor 1 modulates the phosphorylation, expression, and activity of organic anion transporter 3 through protein kinase A signaling pathway

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Acta Pharmaceutica Sinica B 2020年第1期10卷 186-194页

作者： Jinghui Zhang Zhou Yu Guofeng You Department of Pharmaceutics RutgersThe State University of New JerseyPiscatawayNJ 08854USA

Organic anion transporter 3(OAT3)plays a vital role in removing a broad variety of anionic drugs from kidney,thus avoiding their possible toxicity in the *** the current study,we investigated the role of insulin-like growth factor 1(IGF-1)in the regulation of *** showed that IGF-1 induced a dose-and time-dependent increase in OAT3 transport activity,which correlated well with an increase in OAT3 *** IGF-1-induced increase in OAT3 expression was blocked by protein kinase A(PKA)inhibitor ***,IGF-1 induced an increase in OAT3 phosphorylation,which was also blocked by *** data suggest that the IGF-1 modulation of OAT3 occurred through PKA signaling *** further confirm the involvement of PKA,we treated OAT3-expressing cells with PKA activator Bt’2-cAMP,followed by examining OAT activity and *** showed that OAT3 activity and phosphorylation were much enhanced in Bt2-cAMP-treated cells as compared to that in control ***,linsitinib,an anticancer drug that blocks the IGF-1 receptor,abrogated IGF-1-stimulated OAT3 transport *** conclusion,our study demonstrated that IGF-1 regulates OAT3 expression and transport activity through PKA signaling pathway,possibly by phosphorylating the transporter.

关键词： Organic anion transporter Drug transport Regulation IGF-1 PKA Phosphorylation

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Regulation of mitochondrial NAD pool via NAD^+ transporter 2 is essential for matrix NADH homeostasis and ROS production in Arabidopsis

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Science China(Life Sciences) 2019年第8期62卷 991-1002页

作者： Lilan Luo Yajun He Yannan Zhao Qian Xu Jian Wu Haiyan Ma Hongyan Guo Lin Bai Jianru Zuo Jian-Min Zhou Hong Yu Jiayang Li State Key Laboratory of Plant Genomics and National Center for Plant Gene Research Institute of Genetics and Developmental BiologyTheInnovative Academy of Seed DesignChinese Academy of SciencesBeijing100101China University of Chinese Academy of Sciences Beijing100049China Department of Plant Sciences Weizmann Institute of ScienceRehovot 7610001Israel

Reactive oxygen species(ROS) play a crucial role in numerous biological processes in plants, including development, responses to environmental stimuli, and programmed cell death(PCD). Deficiency in MOSAIC DEATH 1(MOD1), a plastid-localized enoyl-ACP reductase essential for de novo fatty acid biosynthesis in Arabidopsis thaliana, leads to the increased malate export from chloroplasts to mitochondria, and the subsequent accumulation of mitochondria-generated ROS and PCD. In this study, we report the identification and characterization of a mod1 suppressor, som592. SOM592 encodes mitochondrion-localized NAD^+ transporter 2(NDT2). We show that the mitochondrial NAD pool is elevated in the mod1 mutant. The som592 mutation fully suppressed mitochondrial NADH hyper-accumulation, ROS production, and PCD in the mod1 mutant, indicating a causal relationship between mitochondrial NAD accumulation and ROS/PCD phenotypes. We also show that in wild-type plants, the mitochondrial NAD+uptake is involved in the regulation of ROS production in response to continuous photoperiod. Elevation of the alternative respiration pathway can suppress ROS accumulation and PCD in mod1, but leads to growth restriction. These findings uncover a regulatory mechanism for mitochondrial ROS production via NADH homeostasis in Arabidopsis thaliana that is likely important for growth regulation in response to altered photoperiod.

关键词： mitochondrial NAD pool NAD^+ transporter 2 mtROS

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OsNPF3.1,a nitrate,abscisic acid and gibberellin transporter gene,is essential for rice tillering and nitrogen utilization efficiency

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Journal of Integrative Agriculture 2024年第4期23卷 1087-1104页

作者： Junnan Hang Bowen Wu Diyang Qiu Guo Yang Zhongming Fang Mingyong Zhang Institute of Rice Industry Technology Research/Key Laboratory of Functional Agriculture Guizhou Provincial Department of Education/Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous RegionMinistry of Education/Key Laboratory of Molecular Breeding for Grain and Oil Crops in Guizhou Province/College of Agricultural SciencesGuizhou UniversityGuiyang 550025China Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement/Guangdong Provincial Key Laboratory of Applied Botany/South China Botanical Garden Chinese Academy of SciencesGuangzhou 510650China Institute of Fruit Tree Research Guangdong Academy of Agricultural SciencesGuangzhou 510640China

Low-affinity nitrate transporter genes have been identified in subfamilies 4-8 of the rice nitrate transporter 1(NRT1)/peptide transporter family(NPF),but the OsNPF3 subfamily responsible for nitrate and phytohormone transport and rice growth and development remains *** this study,we described OsNPF3.1 as an essential nitrate and phytohormone transporter gene for rice tillering and nitrogen utilization efficiency(NUtE).OsNPF3.1 possesses four major haplotypes of its promoter sequence in 517 cultivars,and its expression is positively associated with tiller *** expression was higher in the basal part,culm,and leaf blade than in other parts of the plant,and was strongly induced by nitrate,abscisic acid(ABA)and gibberellin 3(GA_3)in the root and shoot of *** experiments demonstrated that OsNPF3.1 is a pH-dependent low-affinity nitrate transporter,with rice protoplast uptake assays showing it to be an ABA and GA_3 ***3.1 overexpression significantly promoted ABA accumulation in the roots and GA accumulation in the basal part of the plant which inhibited axillary bud outgrowth and rice tillering,especially at high nitrate *** NUtE of OsNPF3.1-overexpressing plants was enhanced under low and medium nitrate concentrations,whereas the NUtE of OsNPF3.1 clustered regularly interspaced short palindromic repeats(CRISPR)plants was increased under high nitrate *** results indicate that OsNPF3.1 transports nitrate and phytohormones in different rice tissues under different nitrate *** altered OsNPF3.1 expression improves NUtE in the OsNPF3.1-overexpressing and CRISPR lines at low and high nitrate concentrations,respectively.

关键词： rice tillering grain yield phytohormone nitrate transporter nitrogen utilization efficiency

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Organic anion transporter 1 and 3 contribute to traditional Chinese medicine-induced nephrotoxicity

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Chinese Journal of Natural Medicines 2020年第3期18卷 196-205页

作者： SHEN Qing-Qing WANG Jing-Jing ROY Debmalya SUN Li-Xin JIANG Zhen-Zhou ZHANG Lu-Yong HUANG Xin Jiangsu Key Laboratory of Drug Screening China Pharmaceutical UniversityNanjing 210009China Jiangsu Center for Pharmacodynamics Research and Evaluation China Pharmaceutical UniversityNanjing 210009China Key Laboratory of Drug Quality Control and Pharmacovigilance Ministry of EducationChina Pharmaceutical UniversityNanjing 210009China Center for Drug Screening and Pharmacodynamics Evaluation School of PharmacyGuangdong Pharmaceutical UniversityGuangzhou 510006China

With the internationally growing popularity of traditional Chinese medicine(TCM), TCM-induced nephropathy has attracted public attention. Minimizing this toxicity is an important issue for future research. Typical nephrotoxic TCM drugs such as Aristolochic acid, Tripterygium wilfordii Hook. f, Rheum officinale Baill, and cinnabar mainly damage renal proximal tubules or cause interstitial nephritis. transporters in renal proximal tubule are believed to be critical in the disposition of xenobiotics. In this review, we provide information on the alteration of renal transporters by nephrotoxic TCMs, which may be helpful for understanding the nephrotoxic mechanism of TCMs and reducing adverse effects. Studies have proven that when administering nephrotoxic TCMs, the expression or function of renal transporters is altered, especially organic anion transporter 1 and 3. The alteration of these transporters may enhance the accumulation of toxic drugs or the dysfunction of endogenous toxins and subsequently sensitize the kidney to ***-related drug combination and clinical biomarkers supervision to avoid the risk of future toxicity are proposed.

关键词： Traditional Chinese medicine Nephrotoxicity Renal tubular epithelial cell Organic anion transporter Aristolochic acid Tripterygium wilfordii Hook.f. Rheum officinale Baill

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The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2

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Protein & Cell 2019年第6期10卷 436-449页

作者： Xinhui Wang Hong Gao Wenhui Wu Enjun Xie Yingying Yu Xuyan He Jin Li Wanru Zheng Xudong Wang Xizhi Cao Zhuoxian Meng Ligong Chen Junxia Min Fudi Wang School of Public Health The First Affiliated Hospital Institute of Translational Medicine Zhejiang University School of Medicine Hangzhou 310058 China School of Pharmaceutical Sciences State Key Laboratory of Membrane Biology Tsinghua-Peking Center for Life Sciences School of Life Sciences Tsinghua University Beijing 100084 China Department of Pathology and Pathophysiology Key Laboratory of Disease Proteomics of Zhejiang Province Zhejiang University School of Medicine Hangzhou 310058 China

Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover,β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.

关键词： zinc zinc transporter pancreatic islets β-cells insulin secretion

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Emerging transporter-targeted nanoparticulate drug delivery systems

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Acta Pharmaceutica Sinica B 2019年第1期9卷 49-58页

作者： Hongyan Su Yan Wang Shuo Liu Yue Wang Qian Liu Guangxuan Liu Qin Chen Department of Pharmacy Cancer Hospital of China Medical University Liaoning Cancer Hospital & Institute

transporter-targeted nanoparticulate drug delivery systems(nano-DDS) have emerged as promising nanoplatforms for efficient drug delivery. Recently, great progress in transporter-targeted strategies has been made, especially with the rapid developments in nanotherapeutics. In this review, we outline the recent advances in transporter-targeted nano-DDS. First, the emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery are reviewed. These include improvements in the oral absorption of protein and peptide drugs, facilitating the intravenous-to-oral switch in cancer chemotherapy. Secondly, the recent advances in transporter-assisted brain-targeting nano-DDS are discussed,focusing on the specific transporter-based targeting strategies. Recent developments in transportermediated tumor-targeting drug delivery are also discussed. Finally, the possible transport mechanisms involved in transporter-mediated endocytosis are highlighted, with special attention to the latest findings of the interactions between membrane transporters and nano-DDS.

关键词： transporter Nano-DDS Oral delivery Brain-targeting Tumor-targeting

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The Plastid Envelope CHLOROPLAST MANGANESE transporter1 Is Essential for Manganese Homeostasis in Arabidopsis

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Molecular Plant 2018年第7期11卷 955-969页

作者： Marion Eisenhut Natalie Hoecker Sidsel Birkelund Schmidt Rubek Merina Basgaran Samantha Flachbart Peter Jahns Tabea Eser Stefan Geimer Seren Husted Andreas P.M. Weber Dario Leister Anja Schneider Biochemie der Pflanzen Cluster of Excellence on Plant Science (CEPLAS) Heinrich-Heine-University Di3sseldorf 40225 Desseldorf Germany Molekularbiologie der Pflanzen (Botanik) Department Biologie I Ludwig-Maximilians-University Mernchen 82152 Martinsried Germany Department of Plant and Environmental Sciences and Copenhagen Plant Science Centre (CPSC) Faculty of Science University of Copenhagen 1871 Frederiksberg Denmark Zellbiologie/Elektronenmikroskopie NW I/B1 Universit&t Bayreuth 95447 Bayreuth Germany These authors contributed equally to this article.

The transition metal manganese （Mn） is indispensable for photoautotrophic growth since photosystem II （PSII） employs an inorganic Mn4CaOs cluster for water splitting. Here, we show that the Arabidopsis membrane protein CHLOROPLAST MANGANESE transporter1 （CMT1） is involved in chloroplast Mn homeostasis. CMT1 is the closest homolog of the previously characterized thylakoid Mn transporter PHOTOSYNTHESIS-AFFECTED MUTANT71 （PAM71）. In contrast to PAM71, CMT1 resides at the chloro- plast envelope and is ubiquitously expressed. Nonetheless, like PAM71, the expression of CMT1 can also alleviate the Mn-sensitive phenotype of yeast mutant qomrl. The cmtl mutant is severely suppressed in growth, chloroplast ultrastructure, and PSII activity owing to a decrease in the amounts of pigments and thylakoid membrane proteins. The importance of CMT1 for chloroplast Mn homeostasis is demonstratedby the significant reduction in chloroplast Mn concentrations in cmtl-1, which exhibited reduced Mn binding in PSII complexes. Moreover, CMT1 expression is downregulated in Mn-surplus conditions. The pam71 cmtl-ldouble mutant resembles the cmtl-f single mutant rather than pare71 in most respects. Taken together, our results suggest that CMT1 mediates Mn2 uptake into the chloroplast stroma, and that CMT1 and PAM71 function sequentially in Mn delivery to PSII across the chloroplast envelope and the thylakoid membrane.

关键词： manganese transporter envelope chloroplast photosynthesis Arabidopsis

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Further study on Ca_(2+) -mediated inhibition of human erythrocyte D-glucose transporter

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Chinese Science Bulletin 1997年第10期42卷 871-875页

作者： XIE Wensheng, TU Yaping and YANG FuyuState Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China State Key Laboratory of Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing China

THE transport of D-glucose to erythrocytes is catalyzed by an integral membrane protein,*** D-glucose *** specifically carries D-glucose,driven by glucose’s *** of its relative abundance and higher transport activity... 详细信息

关键词： Ca2+ glucose transporter transporting activity inhibition.

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