생명과학회지 (Journal of Life Science)

  • 제18권7호
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  • Pages.918-923
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  • 2008
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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항고혈압 치료제 로사탄에 의해 인산화 되는 단백질 발굴

Identification of Phosphoproteins Induced by AT1 Receptor Blocker Losartan

  • 발행 : 2008.07.30
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초록

안지오텐신II 수용체(AT1 수용체)는 혈관수축과 체내 전해질이온 조절에 중요한 역할을 한다. AT1 수용체 길항제(ARB)는 고혈압 치료에 이용되며 최근에는 당뇨병을 포함한 대사질환에 효능이 있음이 알려져 있다. 이 연구에서는 ARB 처리 후 세포 내 인산화단백질에 인산화가 일어나는지를 antibody array를 이용하여 실험하였다. 아미노산세린 및 트레오닌에 인산화되는 단백질 6개, 티로신에 인산화되는 단백질 12개에 대한 항체를 선정하여 nitrocellulose membrane에 부착시켰다. AT1 수용체를 발현한 COS-1 세포에 로사틴(losartan)을 처리하였을 때 small GTPase인 RhoA의 세린 잔기에 인산화가 20% 증가함을 관찰하였다. RhoA는 세포골격의 재배열에 중요한 역할을 하며 세린 잔기에 인산화가 되면 활성이 억제된다. 본 연구결과로부터 ARB가 AT1 수용체에 의한 혈관수축을 억제할 뿐만 아니라 새로운 세포 신호룰 생성함을 알 수 있다.

The angiotensin II receptor ($AT_1R$) antagonists are effective in treating patients with hypertension and showed beneficial effects in diabetes and other metabolic diseases. The beneficial effects of $AT_1R$ antagonists are mainly considered to be from inhibition of Ang $II-AT_1R$ signaling pathway such as the activation of NADPH oxidase and the generation of reactive oxygen species. In this study, we examined whether antagonist of the $AT_1R$ could account for phosphorylation of proteins in cells using antibody array. We have selected 6 proteins with Ser/Thr-phosphorylation sites and 12 proteins with Tyr-phosphorylation sites based on literature search. Upon $AT_1R$ antagonist losartan treatment to serum-starved COS-1 cells, there was ${\sim}20%$ increase of Ser phosphorylation in small GTPase RhoA. RhoA is known to be responsible for cytoskeleton rearrangement and is down-regulated upon Ser phosphorylation in vivo. Our finding provides a new insight into the mechanism and signaling pathway of the $AT_1R$ antagonist in cells.

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