Format

Send to

Choose Destination
Sci Rep. 2018 Feb 22;8(1):3480. doi: 10.1038/s41598-018-21873-1.

i-mediated TRPC4 activation by polycystin-1 contributes to endothelial function via STAT1 activation.

Kwak M1,2, Hong C3, Myeong J1,2, Park EYJ1,2, Jeon JH1,2, So I4,5.

Author information

1
Department of Physiology and Institute of Dermatological Science, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
2
Department of Biomedicines, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
3
Department of Physiology, School of Medicine, Chosun University, Gwangju, 61452, South Korea.
4
Department of Physiology and Institute of Dermatological Science, Seoul National University College of Medicine, Seoul, 110-799, South Korea. insuk@snu.ac.kr.
5
Department of Biomedicines, Seoul National University College of Medicine, Seoul, 110-799, South Korea. insuk@snu.ac.kr.

Abstract

Hypertension and aneurysm are frequently associated with autosomal dominant polycystic kidney disease (ADPKD) caused by polycystin-1 (PC1) mutations, which is closely related to endothelial dysfunction. PC1 is an atypical G-protein-coupled receptor that activates G-proteins by self-cleavage; currently, however, the molecular and cellular mechanisms of the associated intracellular signaling and ion channel activation remain poorly elucidated. Here, we report an activation mechanism of a calcium-permeable canonical transient receptor potential 4 (TRPC4) channel by PC1 and its endothelial function. We found that the inhibitory Gαi3 protein selectively bound to the G-protein-binding domain on the C-terminus of PC1. The dissociation of Gαi3 upon cleavage of PC1 increased TRPC4 activity. Calcium influx through TRPC4 activated the transcription factor STAT1 to regulate cell proliferation and death. The down-regulation of PC1/TRPC4/STAT1 disrupted migration of endothelial cell monolayers, leading to an increase in endothelial permeability. These findings contribute to greater understanding of the high risk of aneurysm in patients with ADPKD.

PMID:
29472562
PMCID:
PMC5823873
DOI:
10.1038/s41598-018-21873-1
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center