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研究生:李松柏
研究生(外文):Lee Sung-Bau
論文名稱:β-制動素參與蛋白酶激活的接受器1在細胞內移動的過程
論文名稱(外文):Involvement of β-arrestin in Intracellular Trafficking of Protease-activated Receptor 1
指導教授:傅化文傅化文引用關係
指導教授(外文):Fu Hua-Wen
學位類別:碩士
校院名稱:國立清華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:55
中文關鍵詞:β-制動素蛋白酶激活的接受器1細胞內移動G蛋白連結接受器克拉斯林
外文關鍵詞:β-arrestinProtease-activated receptor 1Intracellular TraffickingG protein-coupled receptorClathrin
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蛋白酶激活的接受器1 (protease-activated receptor 1, PAR1) 為一個G蛋白連結接受器 (G protein-coupled receptor, GPCR)。其被凝血蛋白酶 (thrombin) 不可逆的激活後會經由克拉斯林所組成之覆被孔 (clathrin-coated pits) 進入細胞內並於溶酶體 (lysosome) 中分解。此機制對於終止蛋白酶激活的接受器1的訊息傳遞是非常重要的。然而,至今對蛋白酶激活的接受器1進入細胞和送至溶酶體的確切機制並不清楚。許多研究顯示β-制動素 (β-arrestin) 會經由阻斷訊息傳遞的過程而促成許多G蛋白連結接受器的去敏感化作用(desensitization),且調節許多被激活後的G蛋白連結接受器的胞噬作用 (endocytosis)。在此論文中,我探討β-制動素是否有參與於調節蛋白酶激活的接受器1在細胞內移動的過程。我發現當接受器被激活劑 (agonist) 激活後,β-制動素會被快速吸引至細胞膜並與激活後的蛋白酶激活的接受器1共同定位於細胞膜。然後,β-制動素會與激活後的蛋白酶激活的接受器1一起送至早期胞噬囊 (early endosomes)。另外,優勢陰性型 (dominant-negative) 的β-制動素會抑制經激活劑激活後的蛋白酶激活的接受器1進入細胞的過程。這些結果指示出β-制動素會隨著激活後的接受器一起送至早期胞噬囊而調節蛋白酶激活的接受器1在細胞內移動的過程。

Protease-activated receptor 1 (PAR1), a G protein-coupled receptor (GPCR), is irreversibly activated upon thrombin cleavage, then internalized via clathrin-coated pit into the cells and degraded in lysosome. This mechanism is critical for the termination of PAR1 signaling. However, the exact mechanism by which PAR1 is internalized and sorted to lysosome is poorly understood. Many studies show that β-arrestin contributes to the desensitization of many activated GPCRs by uncoupling the signal transduction process and mediates the endocytosis of many activated GPCRs. In this thesis, I investigated whether β-arrestin is involved in regulating the intracellular trafficking of PAR1. I found that β-arrestin was rapidly recruited to cell membrane and colocalized with activated PAR1 after agonist stimulation. Then, β-arrestin was sorted together with PAR1 into early endosomes. In addition, the dominant-negative form of β-arrestin (β-arr319-418) blocked agonist-stimulated internalization of PAR1. These results indicate that β-arrestin is involved in regulating the intracellular trafficking of PAR1 by associating with activated receptor into early endosomes.

Abstract……………………………………………………………………………………………1
中文摘要…………………………...…………………………..………..…………………….….2
Abbreviations……………………………………………………………………………………..3
Introduction…………………………………………………….…………………………..….….5
Materials and Methods…………………………………………………………………………..22
Results…………………………………………………………………………………………...31
Discussion……………………………………………………………………………………….36
References……………………………………………………………………………………….40
Figure 1. Agonist-triggered colocalization of PAR1 and β-arrestin2-GFP at clathrin-coated
pits………………………………………………...………………..………………50
Figure 2. Agonist-triggered colocalization of PAR1 and β-arrestin2-GFP in early endosomes.
……………………………………………………...………………..………...…..51
Figure 3. Effect of dominant-negative β-arrestin on agonist-triggered internalization of PAR1.……………………………………………………...………………..……...52
Figure 4. Effect of dominant-negative β-arrestin on agonist-triggered internalization of PAR1 examined by immunofluorescence microscopy…………....…………………...….53
Figure 5. Effect of dominant-negative β-arrestin on the uptake of transferrin examined by confocal microscopy...…………………………...………………..……………….54
Figure 6. Hypothetical pathway of agonist-triggered trafficking of PAR1 and β-arrestin…….55

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