Search

The transient receptor potential canonical (TRPC) 1 channel is widely distributed in mammalian cells and is involved in many physiological processes. TRPC1 is primarily considered a regulatory subunit that forms heterotetrameric channels with either TRPC4 or TRPC5 subunits. Here, we suggest that the regulation of TRPC1/4 and TRPC1/5 heterotetrameric channels by the Gαq-PLCβ pathway is self-limited and dynamically mediated by Gαq and PI(4,5)P2. We provide evidence indicating that Gαq protein directly interacts with either TRPC4 or TRPC5 of the heterotetrameric channels to permit activation. Simultaneously, Gαq-coupled PLCβ activation leads to the breakdown of PI(4,5)P2, which inhibits activity of TRPC1/4 and 1/5 channels. [ABSTRACT FROM AUTHOR]

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.