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

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...

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Autores principales:	Misun Kwak, Chansik Hong, Jongyun Myeong, Eunice Yon June Park, Ju-Hong Jeon, Insuk So
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6b1dac94af454f40b779ad80c02bde32
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spelling	oai:doaj.org-article:6b1dac94af454f40b779ad80c02bde322021-12-02T15:09:06ZGαi-mediated TRPC4 activation by polycystin-1 contributes to endothelial function via STAT1 activation10.1038/s41598-018-21873-12045-2322https://doaj.org/article/6b1dac94af454f40b779ad80c02bde322018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21873-1https://doaj.org/toc/2045-2322Abstract 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.Misun KwakChansik HongJongyun MyeongEunice Yon June ParkJu-Hong JeonInsuk SoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Misun Kwak Chansik Hong Jongyun Myeong Eunice Yon June Park Ju-Hong Jeon Insuk So Gαi-mediated TRPC4 activation by polycystin-1 contributes to endothelial function via STAT1 activation
description	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.
format	article
author	Misun Kwak Chansik Hong Jongyun Myeong Eunice Yon June Park Ju-Hong Jeon Insuk So
author_facet	Misun Kwak Chansik Hong Jongyun Myeong Eunice Yon June Park Ju-Hong Jeon Insuk So
author_sort	Misun Kwak
title	Gαi-mediated TRPC4 activation by polycystin-1 contributes to endothelial function via STAT1 activation
title_short	Gαi-mediated TRPC4 activation by polycystin-1 contributes to endothelial function via STAT1 activation
title_full	Gαi-mediated TRPC4 activation by polycystin-1 contributes to endothelial function via STAT1 activation
title_fullStr	Gαi-mediated TRPC4 activation by polycystin-1 contributes to endothelial function via STAT1 activation
title_full_unstemmed	Gαi-mediated TRPC4 activation by polycystin-1 contributes to endothelial function via STAT1 activation
title_sort	gαi-mediated trpc4 activation by polycystin-1 contributes to endothelial function via stat1 activation
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/6b1dac94af454f40b779ad80c02bde32
work_keys_str_mv	AT misunkwak gaimediatedtrpc4activationbypolycystin1contributestoendothelialfunctionviastat1activation AT chansikhong gaimediatedtrpc4activationbypolycystin1contributestoendothelialfunctionviastat1activation AT jongyunmyeong gaimediatedtrpc4activationbypolycystin1contributestoendothelialfunctionviastat1activation AT euniceyonjunepark gaimediatedtrpc4activationbypolycystin1contributestoendothelialfunctionviastat1activation AT juhongjeon gaimediatedtrpc4activationbypolycystin1contributestoendothelialfunctionviastat1activation AT insukso gaimediatedtrpc4activationbypolycystin1contributestoendothelialfunctionviastat1activation
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Gαi-mediated TRPC4 activation by polycystin-1 contributes to endothelial function via STAT1 activation

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