Organic anion transporters(OATs)and organic anion transporter polypeptides(OATPs)are classified within two SLC superfamilies,namely,the SLC22A superfamily and the SLCO superfamily(formerly the SLC21A family),respectiv...Organic anion transporters(OATs)and organic anion transporter polypeptides(OATPs)are classified within two SLC superfamilies,namely,the SLC22A superfamily and the SLCO superfamily(formerly the SLC21A family),respectively.They are expressed in many tissues,such as the liver and kidney,and mediate the absorption and excretion of many endogenous and exogenous substances,including various drugs.Most are composed of 12 transmembrane polypeptide chains with the C-terminus and the N-terminus located in the cell cytoplasm.OATs and OATPs are abundantly expressed in the liver,where they mainly promote the uptake of various endogenous substrates such as bile acids and various exogenous drugs such as antifibrotic and anticancer drugs.However,differences in the locations of glycosylation sites,phosphorylation sites,and amino acids in the OAT and OATP structures lead to different substrates being transported to the liver,which ultimately results in their different roles in the liver.To date,few articles have addressed these aspects of OAT and OATP structures,and we study further the similarities and differences in their structures,tissue distribution,substrates,and roles in liver diseases.展开更多
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 body.In the current study,we investigated the role of insulin-l...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 body.In the current study,we investigated the role of insulin-like growth factor 1(IGF-1)in the regulation of OAT3.We showed that IGF-1 induced a dose-and time-dependent increase in OAT3 transport activity,which correlated well with an increase in OAT3 expression.The IGF-1-induced increase in OAT3 expression was blocked by protein kinase A(PKA)inhibitor H89.Moreover,IGF-1 induced an increase in OAT3 phosphorylation,which was also blocked by H89.These data suggest that the IGF-1 modulation of OAT3 occurred through PKA signaling pathway.To further confirm the involvement of PKA,we treated OAT3-expressing cells with PKA activator Bt’2-cAMP,followed by examining OAT activity and phosphorylation.We showed that OAT3 activity and phosphorylation were much enhanced in Bt2-cAMP-treated cells as compared to that in control cells.Finally,linsitinib,an anticancer drug that blocks the IGF-1 receptor,abrogated IGF-1-stimulated OAT3 transport activity.In conclusion,our study demonstrated that IGF-1 regulates OAT3 expression and transport activity through PKA signaling pathway,possibly by phosphorylating the transporter.展开更多
GABA transporter 1(GAT1) takes important roles in multiple physiological processes through the uptake and release of GABA, but the regulation of GAT1 gene expression in different tissues is rarely known. To address th...GABA transporter 1(GAT1) takes important roles in multiple physiological processes through the uptake and release of GABA, but the regulation of GAT1 gene expression in different tissues is rarely known. To address the question, first, 5’ Rapid amplification of cDNA end (RACE) was used to determine GAT1 transcriptional starting sites in neonatal mouse cerebral cortex and intestine, adult mouse brain and adult rat testis. The products of 5’RACE were confirmed by DNA sequencing. We found that the transcript of GAT1 in neonatal mouse cerebral cortex and adult mouse brain starts at the same site (inside of exon 1), while in mouse intestine, GAT1 starts transcription in intron 1, and in rat testis, the transcript of GAT1 has an additional untranslation exon to the 5’ direction.展开更多
MOLECULAR PHYSIOLLGY OF HEPATOCELLULAR TRANSPORT PROTEINS Basolaferal transport systems Na+-dependent bile salt uptake Uptake of bile salts into the liver was first isolated perfused rat liver[1],isolated hepatocyte...MOLECULAR PHYSIOLLGY OF HEPATOCELLULAR TRANSPORT PROTEINS Basolaferal transport systems Na+-dependent bile salt uptake Uptake of bile salts into the liver was first isolated perfused rat liver[1],isolated hepatocyte cultures and basolateral plasma membrane vesicles [2,4].展开更多
胆红素作为人体的一种重要内源性物质,是临床诊断黄疸的主要依据,也是肝功能的重要指标。本文在简述胆红素代谢过程、代谢动力学及代谢异常的基础上,重点对有机阴离子转运多肽(organic anion transport polypeptide.OATP)和多药耐药相...胆红素作为人体的一种重要内源性物质,是临床诊断黄疸的主要依据,也是肝功能的重要指标。本文在简述胆红素代谢过程、代谢动力学及代谢异常的基础上,重点对有机阴离子转运多肽(organic anion transport polypeptide.OATP)和多药耐药相关蛋白(multidrug-associated protein.MRP)等转运体介导的胆红素转运、PXR和CAR等核受体对UGTlAl介导的胆红素代谢调控、药物对胆红素代谢的抑制和诱导,及其与胆红素相关病症关系等方面的最新进展进行归纳和总结,为进一步研究和揭示黄疸、高胆红素血症、新生儿黄疸等胆红素相关病症的发生原因和发生机制提供参考,并为其诊断、预防和治疗提供最新科学依据。展开更多
文摘Organic anion transporters(OATs)and organic anion transporter polypeptides(OATPs)are classified within two SLC superfamilies,namely,the SLC22A superfamily and the SLCO superfamily(formerly the SLC21A family),respectively.They are expressed in many tissues,such as the liver and kidney,and mediate the absorption and excretion of many endogenous and exogenous substances,including various drugs.Most are composed of 12 transmembrane polypeptide chains with the C-terminus and the N-terminus located in the cell cytoplasm.OATs and OATPs are abundantly expressed in the liver,where they mainly promote the uptake of various endogenous substrates such as bile acids and various exogenous drugs such as antifibrotic and anticancer drugs.However,differences in the locations of glycosylation sites,phosphorylation sites,and amino acids in the OAT and OATP structures lead to different substrates being transported to the liver,which ultimately results in their different roles in the liver.To date,few articles have addressed these aspects of OAT and OATP structures,and we study further the similarities and differences in their structures,tissue distribution,substrates,and roles in liver diseases.
基金supported by grants(to Dr.Guofeng You)from National Institute of General Medical Sciences(R01-GM079123 and R01-GM097000,USA).
文摘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 body.In the current study,we investigated the role of insulin-like growth factor 1(IGF-1)in the regulation of OAT3.We showed that IGF-1 induced a dose-and time-dependent increase in OAT3 transport activity,which correlated well with an increase in OAT3 expression.The IGF-1-induced increase in OAT3 expression was blocked by protein kinase A(PKA)inhibitor H89.Moreover,IGF-1 induced an increase in OAT3 phosphorylation,which was also blocked by H89.These data suggest that the IGF-1 modulation of OAT3 occurred through PKA signaling pathway.To further confirm the involvement of PKA,we treated OAT3-expressing cells with PKA activator Bt’2-cAMP,followed by examining OAT activity and phosphorylation.We showed that OAT3 activity and phosphorylation were much enhanced in Bt2-cAMP-treated cells as compared to that in control cells.Finally,linsitinib,an anticancer drug that blocks the IGF-1 receptor,abrogated IGF-1-stimulated OAT3 transport activity.In conclusion,our study demonstrated that IGF-1 regulates OAT3 expression and transport activity through PKA signaling pathway,possibly by phosphorylating the transporter.
基金foundations from Chinese Academy of Sciences and Special Funds for Major State Basic reseaxch of China (G1999053903).
文摘GABA transporter 1(GAT1) takes important roles in multiple physiological processes through the uptake and release of GABA, but the regulation of GAT1 gene expression in different tissues is rarely known. To address the question, first, 5’ Rapid amplification of cDNA end (RACE) was used to determine GAT1 transcriptional starting sites in neonatal mouse cerebral cortex and intestine, adult mouse brain and adult rat testis. The products of 5’RACE were confirmed by DNA sequencing. We found that the transcript of GAT1 in neonatal mouse cerebral cortex and adult mouse brain starts at the same site (inside of exon 1), while in mouse intestine, GAT1 starts transcription in intron 1, and in rat testis, the transcript of GAT1 has an additional untranslation exon to the 5’ direction.
基金supported by"H+Die Spitaler der Schweiz" the Swiss Agency for Development and Cooperation(DEZA)by the University Hospital Zurich/Switzerland
文摘MOLECULAR PHYSIOLLGY OF HEPATOCELLULAR TRANSPORT PROTEINS Basolaferal transport systems Na+-dependent bile salt uptake Uptake of bile salts into the liver was first isolated perfused rat liver[1],isolated hepatocyte cultures and basolateral plasma membrane vesicles [2,4].
文摘胆红素作为人体的一种重要内源性物质,是临床诊断黄疸的主要依据,也是肝功能的重要指标。本文在简述胆红素代谢过程、代谢动力学及代谢异常的基础上,重点对有机阴离子转运多肽(organic anion transport polypeptide.OATP)和多药耐药相关蛋白(multidrug-associated protein.MRP)等转运体介导的胆红素转运、PXR和CAR等核受体对UGTlAl介导的胆红素代谢调控、药物对胆红素代谢的抑制和诱导,及其与胆红素相关病症关系等方面的最新进展进行归纳和总结,为进一步研究和揭示黄疸、高胆红素血症、新生儿黄疸等胆红素相关病症的发生原因和发生机制提供参考,并为其诊断、预防和治疗提供最新科学依据。
