کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10815055 | 1058444 | 2015 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
EHT 1864, a small molecule inhibitor of Ras-related C3 botulinum toxin substrate 1 (Rac1), attenuates glucose-stimulated insulin secretion in pancreatic β-cells
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کلمات کلیدی
CDC42geranylgeranyl transferase inhibitorSmall G-proteinsADP-ribosylation factor 6ARF6GSISNox2GEFGGTIRac1GTPERK1/2 - ERK1 / 2NADPH oxidase 2 - NADPH اکسیداز 2Insulin secretion - ترشح انسولینGDP - تولید ناخالص ملیPancreatic islet - جزیره پانکراسRas-related C3 botulinum toxin substrate 1 - زیر بغل سم بوتولینوم C3 مرتبط با ریز 1guanine nucleotide exchange factor - فاکتور تبادل نوکلئوتید گوانینcell division control protein 42 - پروتئین کنترل تقسیم سلولی 42extracellular signal-regulated kinases - کیناز های تنظیم شده سیگنال خارج سلولیhigh glucose - گلوکز بالا یا قند بالاGlucose stimulated insulin secretion - گلوکز ترشح انسولین را تحریک می کندlow glucose - گلوکز پایینGuanosine triphosphate - گوانوزین تری فسفاتguanosine diphosphate - گوانوزین دی فسفات
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Glucose-stimulated insulin secretion (GSIS) in the pancreatic β-cells entails a variety of signaling mechanisms including activation of small GTP-binding proteins (G-proteins). Previous studies from our laboratory in human islets, rodent islets and clonal β-cells have demonstrated that G-proteins (e.g., Arf6, Cdc42 and Rac1) play novel roles in cytoskeletal remodeling, which is a critical step in the trafficking of insulin-laden secretory granules for fusion with plasma membrane and release of insulin. To further understand regulatory roles of Rac1 in GSIS, we utilized, herein, EHT 1864, a small molecule inhibitor, which attenuates Rac1 activation by retaining the G-protein in an inert/inactive state, thereby preventing activation of its downstream effector proteins. We demonstrate that EHT 1864 markedly attenuated GSIS in INS-1 832/13 cells. In addition, EHT 1864 significantly reduced glucose-induced activation and membrane targeting of Rac1 in INS-1 832/13 cells. This Rac1 inhibitor also suppressed glucose-induced activation of ERK1/2 and p53, but not Akt. Lastly, unlike the inhibitors of protein prenylation (simvastatin), EHT 1864 did not exert any significant effects on cell morphology (cell rounding) under the conditions it attenuated Rac1-sensitive signaling steps leading to GSIS. Based on these findings, we conclude that EHT 1864 specifically inhibits glucose-induced Rac1 activation and membrane association and associated downstream signaling events culminating in inhibition of GSIS.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 27, Issue 6, June 2015, Pages 1159-1167
Journal: Cellular Signalling - Volume 27, Issue 6, June 2015, Pages 1159-1167
نویسندگان
Vaibhav Sidarala, Rajakrishnan Veluthakal, Khadija Syeda, Anjaneyulu Kowluru,