کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5823915 | 1118373 | 2012 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Residue Ile89 in human plasma membrane monoamine transporter influences its organic cation transport activity and sensitivity to inhibition by dilazep
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کلمات کلیدی
FACSENTVmax1-methyl-4-phenylpyridiniumYFPSLC22MDCKNBMPRPMATMPP+ - MPP +Oct - اکتبرequilibrative nucleoside transporter - ترانسفورماتور نوکلئوتیدی تعادلorganic cation transporter - حمل و نقل کاتیونی آلیtransmembrane domain - دامنه فرابنفشDilazep - دیلازپdipyridamole - دیپیریدامولplasma membrane monoamine transporter - غشای پلاسما مونوآمینfluorescence activated cell sorting - فلورسانس سلول فعال فعال سلولnitrobenzylmercaptopurine riboside - نیتروبنزیل مروپاپورپورین ریبوزیدYellow Fluorescence Protein - پروتئین فلورسانس زردMadin–Darby Canine Kidney - کلیه کلیوی کلیوی Madin-Darby
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Plasma membrane monoamine transporter (PMAT) is a polyspecific organic cation transporter belonging to the equilibrative nucleoside transporter (ENT) family. Despite its distinct substrate specificity from the classic nucleoside transporters ENT1 and 2, PMAT appears to share similar protein architecture with ENT1/2 and retains low affinity binding to classic ENT inhibitors such as nitrobenzylmercaptopurine riboside (NBMPR) and the coronary vasodilators dilazep and dipyridamole. Here we investigated the role of residue Ile89, a position known to be important for ENT interaction with dilazep, dipyridamole, and nucleoside substrates, in PMAT transport function and its interaction with classic ENT inhibitors using Madin-Darby canine kidney (MDCK) cells stably expressing human PMAT. Substitution of Ile89 in PMAT with Met, the counterpart residue in ENT1, resulted in normal plasma membrane localization and protein expression. Transport kinetic analysis revealed that I89M mutant had a 2.7-fold reduction in maximal transport velocity (Vmax) with no significant change in apparent binding affinity (Km) towards the prototype PMAT substrate 1-methyl-4-phenylpyridinium (MPP+), suggesting that I89 is an important determinant for the catalytic activity of PMAT. Dose-dependent inhibition studies further showed that the I89M mutation significantly increased PMAT's sensitivity to dilazep by 2.5-fold without affecting its sensitivity to dipyridamole and NBMPR. Located at the extracellular end of transmembrane domain 1 of PMAT, I89 may occupy an important position close to the substrate permeation pathway and may be involved in direct interaction with the vasodilator dilazep.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 84, Issue 3, 1 August 2012, Pages 383-390
Journal: Biochemical Pharmacology - Volume 84, Issue 3, 1 August 2012, Pages 383-390
نویسندگان
Horace T.B. Ho, Li Xia, Joanne Wang,