S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biomedical Sciences (대학원 의과학과) Theses (Ph.D. / Sc.D._의과학과)
Mechanism of TRPC4 activation by polycystin-1 and its regulation of Ca2+-dependent signals in endothelium
폴리시스틴-1에 의한 TRPC4 이온통로 활성화 기전 및 내피세포의 칼슘의존성 신호전달 조절
- 의과대학 의과학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2017. 2. 서인석.
- Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder caused by polycystin-1 and polycystin-2 mutations. Hypertension and aneurysm are frequently associated with polycystic kidney disease, which is closely related to endothelial dysfunction. Polycystin-1 is an atypical G protein-coupled receptor that activates G protein by self-cleavage, induces intracellular signaling via activated G protein, and cell response by ion channel activation has been reported. TRPC4 is a calcium-permeable cation channel and is activated by a specific subtype of G protein (Gαi). In this study, I hypothesized that polycystin-1 acts as a G protein-coupled receptor and activates G protein, resulting in TRPC4 activity. The C-terminus of polycystin-1 contains a G protein binding domain and selectively bound to Gαi3 among the inhibitory G protein subtypes. The increase of TRPC4 activity by polycystin-1 was mediated by Gαi3 and its mechanism was found to be the dissociation of the Gαi3 from cleavage of PC1 C-terminus. Calcium influx through TRPC4 activated signal transducer and activator of transcription (STAT) and nuclear factor of activated T cells (NFAT) transcription factor to regulate cell proliferation and death. In endothelial cells, endogenous expression and calcium influx of polycystin-1 and TRPC4 were observed. Inhibition of their expression or antagonist inhibited endothelial cell migration and weakened endothelial junctions. These results suggest that TRPC4 activity by polycystin-1 is important for endothelial cell monolayer formation and permeability through endothelial cells, and that TRPC4 is a target in the mechanism and treatment of aneurysms associated with ADPKD.