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The physiological role of drug transporters

Protein & Cell 2015年第5期6卷 334-350页

作者： Yu Liang Siqi Li Ligong Chen Department of Pharmacology and Pharmaceutical Sciences School of Medicine Tsinghua University Beijing 100084 China Collaborative Innovation Center for Biotherapy State Key Laboratory of Biotherapy and Cancer Center West China Hospital West China Medical School Sichuan University Chengdu 610041 China

Transporters comprise the largest family of membrane proteins in human organism, including members of solute carrier transporter and ATP-binding cassette transporter families. They play pivotal roles in the absorption, distribution and excretion of xenobiotic and endogenous molecules. Transporters are widely expressed in various human tissues and are routinely evaluated during the process of drug development and approval. Over the past decade, increasing evidence shows that drug transporters are important in both normal physiology and disease. Currently, transporters are utilized as therapeutic targets to treat numerous diseases such as diabetes, major depression, hypertension and constipation. Despite the steady growth of the field of transporter biology, more than half of the members in transporter superfamily have little information available about their endogenous substrate（s） or physiological functions. This review outlines current research methods in transporter studies, and summarizes the drug-transporter interactions including drug-drug and drug-endogenous substrate interactions. In the end, we also discuss the therapeutic perspective of transporters based on their physiological and pathophysiological roles.

关键词： transporter physiological role therapeuticimplication

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physiological roles of β-amyloid in Regulating Synaptic Function:Implications for AD Pathophysiology

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神经科学通报:英文版 2023年第8期39卷 1289-1308页

作者： Wenwen Cai Linxi Li Shaoming Sang Xiaoli Pan Chunjiu Zhong Department of Neurology Zhongshan HospitalFudan UniversityShanghai 200032China Basic Medical College Nanchang UniversityNanchang 330031China State Key Laboratory of Medical Neurobiology Institutes of Brain Science&Collaborative Innovation Center for Brain ScienceFudan UniversityShanghai 200032China

The physiological functions of endogenous amyloid-β(Aβ),which plays important role in the pathology of Alzheimer's disease(AD),have not been paid enough attention.Here,we review the multiple physiological effects of Aβ,particularly in regulating synaptic transmission,and the possible mechanisms,in order to decipher the real characters of Aβunder both physiological and pathological conditions.Some worthy studies have shown that the deprivation of endogenous Aβgives rise to synaptic dysfunction and cognitive deficiency,while the moderate elevation of this peptide enhances long term potentiation and leads to neuronal hyperexcitability.In this review,we provide a new view for understanding the role of Aβin AD pathophysiology from the perspective of physiological meaning.

关键词： Aβ physiological role Synapse LTP Synaptic vesicle cycle Cognition AD

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Plant Carbonic Anhydrases： Structures, Locations, Evolution, and physiological roles

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Molecular Plant 2017年第1期10卷 30-46页

作者： Robert J. DiMario Harmony Clayton Ananya Mukhedee Martha Ludwig James V. Moroney Department of Biological Sciences Louisiana State University Baton Rouge LA 70803 USA School of Chemistry and Biochemistry University of Western Australia Perth WA 6009 Australia

Carbonic anhydrases （CAs） are zinc metalloenzymes that catalyze the interconversion of CO2 and HCO3- and are ubiquitous in nature. Higher plants contain three evolutionarily distinct CA families, αCAs, 13CAs, and γCAs, where each family is represented by multiple isoforms in all species. Alternative splicing of CA transcripts appears common; consequently, the number of functional CA isoforms in a species may exceed the number of genes. CAs are expressed in numerous plant tissues and in different cellular locations. The most prevalent CAs are those in the chloroplast, cytosol, and mitochondria. This diversity in location is paralleled in the many physiological and biochemical roles that CAs play in plants. In this review, the number and types of CAs in C3, C4, and crassulacean acid metabolism （CAM） plants are considered, and the roles of the α and yCAs are briefly discussed. The remainder of the review focuses on plant βCAs and includes the identification of homologs between species using phylogenetic approaches, a consideration of the inter- and intracellular localization of the proteins, along with the evidence for alternative splice forms. Current understanding of βCA tissue-specific expression patterns and what controls them are reviewed, and the physiological roles for which βCAs have been implicated are presented.

关键词： carbonic anhydrase regulation alternative splicing physiological role

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Complete Alteration of Substrate Specificity of Two Yeast Isocitrate Dehydrogenases by Single-Point Arginine Mutation

Complete Alteration of Substrate Specificity of Two Yeast Is...

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华东六省一市生物化学与分子生物学学会2014年学术交流...

作者：宋平魏焕焕曹正宇王鹏朱国萍安徽师范大学分子生物学及生物技术研究所

Isocitrate dehydrogenase(IDH),as an old housekeeping gene and a popular star,drawing more and more attention of cancer experts.Mutation in catalytic Arg132 residue of human IDH1 changed its substrate specificity from isocitrate(ICT)to a-ketoglutarate(a-KG).To examine whether the analogous mutation could cause similar effects on other eukaryotic NADP-IDH,two yeast NADP-IDHs,Saccharomyces cerevisiae mitochondrial NADP-IDH1(ScIDHl)and Yarrowia lipolytica mitochondrial NADP-IDH(YlIDH),were studied.In the present study,the analogous Arg residues,Arg 148 of ScIDH 1 and Arg 141 of YIIDH,were changed to His,respectively.The K of ScIDHl R148H and YIIDH R141H displayed for isocitrate was evaluated by 3-fold and 2-fold,respectively.The catalytic turnover numbers(k)of ScIDHl R148H and YIIDH R141H toward isocitrate were severely reduced,to only 0.9%and 0.5%of that of wild-type enzyme,respectively.The decreased kleaded to the largely reduced catalytic efficiencies(k/K)of ScIDHl R148H and YIIDH R141H for isocitrate oxidation,dropped to only 0.3%and 0.25%of that of wild-type enzyme.As expected,ScIDHl R148H and YIIDH R141H acquired the neomorphic activity and each of them displayed a 30-fold and 20-fold higher affinity to a-KG than human IDH1 R132H mutant,respectively.However,the kvalues for a-KG of ScIDHl R148H and YIIDH R141H were much smaller(being about 0.04%)than those of human IDH1 mutants.Both mutants displayed a 3-fold preference for a-KG over isocitrate as measured by[k/K]/[k/K],proving that the Arg mutation altered the substrate specificities of both yeast NADP-IDHs.Since the human IDH1 Argl32 mutation is involved in the tumorigenesis,the present study provides the fundamental information for the further research on the physiological role of yeast IDH Arg mutation in vivo.

关键词： isocitrate dehydrogenase arginine mutation tumorigenesis site-directed mutagenesis physiological role GC/TOF-MS

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