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

• Published in: Scientific reports Vol. 8; no. 1; pp. 3480 - 14
• Main Authors: Kwak, Misun, Hong, Chansik, Myeong, Jongyun, Park, Eunice Yon June, Jeon, Ju-Hong, So, Insuk
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.02.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/89; 14/33; 14/35; 38; 38/70; 42; 42/109; 45; 631/80/304; 631/80/86/1999; 631/80/86/2372; 9/74; Aneurysm; C-Terminus; Calcium; Calcium influx; Calcium permeability; Cell death; Cell migration; Cell proliferation; Down-regulation; Endothelial cells; G protein-coupled receptors; Humanities and Social Sciences; Hypertension; Intracellular signalling; Kidney diseases; multidisciplinary; Mutation; Permeability; Polycystic kidney; Polycystic kidney disease 1 protein; Proteins; Science; Science (multidisciplinary); Stat1 protein; Transient receptor potential 4; Transient receptor potential proteins
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-21873-1

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 Gα i3 protein selectively bound to the G-protein-binding domain on the C-terminus of PC1. The dissociation of Gα i3 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.