کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9002176 | 1118576 | 2005 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Role of two adjacent cytoplasmic tyrosine residues in MRP1 (ABCC1) transport activity and sensitivity to sulfonylureas
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کلمات کلیدی
BcrpNBDLTC4E217βGMRP1ABCMTXATP-binding cassette proteinsMRPMSDEstrone 3-sulfateHEKSite-directed mutagenesis - mutagenesis مواجه با سایتsur - برcytoplasmic loop - حلقه سیتوپلاسمیکorganic anion transport - حمل آنیون آلیGlutathione transport - حمل و نقل گلوتاتیونnucleotide binding domain - دامنه اتصال نوکلئوتیدیmembrane spanning domain - دامنه غشاییSulfonylurea - سولفونیل اورهtransmembrane - فرابنفشLeukotriene C4 - لوکوترین C4Methotrexate - متوتروکساتwild-type - نوع وحشیmultidrug resistance protein - پروتئین مقاوم در برابر چندین رژیمbreast cancer resistance protein - پروتئین مقاومت به سرطان سینهhuman embryonic kidney - کلیه جنین انسانATP-binding cassette - کیت اتصال به ATPsulfonylurea receptor - گیرنده سولفونیل اوره
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
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چکیده انگلیسی
The human ATP-binding cassette (ABC) protein MRP1 causes resistance to many anticancer drugs and is also a primary active transporter of conjugated metabolites and endogenous organic anions, including leukotriene C4 (LTC4) and glutathione (GSH). The sulfonylurea receptors SUR1 and SUR2 are related ABC proteins with the same domain structure as MRP1, but serve as regulators of the K+ channel Kir6.2. Despite their functional differences, the activity of both SUR1/2 and MRP1 can be blocked by glibenclamide, a sulfonylurea used to treat diabetes. Residues in the cytoplasmic loop connecting transmembrane helices 15 and 16 of the SUR proteins have been implicated as molecular determinants of their sensitivity to glibenclamide and other sulfonylureas. We have now investigated the effect of mutating Tyr1189 and Tyr1190 in the comparable region of MRP1 on its transport activity and sulfonylurea sensitivity. Ala and Ser substitutions of Tyr1189 and Tyr1190 caused a â¥50% decrease in the ability of MRP1 to transport different organic anions, and a decrease in LTC4 photolabeling. Kinetic analyses showed the decrease in GSH transport was attributable primarily to a 10-fold increase in Km. In contrast, mutations of these Tyr residues had no major effect on the catalytic activity of MRP1. Furthermore, the mutant proteins showed no substantial differences in their sensitivity to glibenclamide and tolbutamide. We conclude that MRP1 Tyr1189 and Tyr1190, unlike the corresponding residues in SUR1, are not involved in its differential sensitivity to sulfonylureas, but nevertheless, may be involved in the transport activity of MRP1, especially with respect to GSH.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 69, Issue 3, 1 February 2005, Pages 451-461
Journal: Biochemical Pharmacology - Volume 69, Issue 3, 1 February 2005, Pages 451-461
نویسندگان
Gwenaëlle Conseil, Roger G. Deeley, Susan P.C. Cole,