P85α regulatory subunit isoform controls PI3-kinase and TRPC6 membrane translocation. (May 2023)

• Record Type: Journal Article
• Authors: Chaudhuri, Pinaki; Putta, Priya; Graham, Linda M.; Rosenbaum, Michael A.
• Is Part Of: Cell calcium. Volume 111(2023)
• Publication Date: 2023-05
• Subjects: Phosphatidylinositol 3-kinase -- p85α -- TRPC6 -- Endothelial cell migration; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2023.102718
• Languages: English
• ISSNs: 0143-4160

Abstract

Highlights: Oxidized lipids selectively activate the PI3K p85α regulatory subunit isoform. p85α isoform selectively controls lysoPC-induced PI3K membrane translocation. p85α-mediated PI3K activation by lysoPC induces TRPC6 translocation and activation. p85α siRNA blocks lysoPC-induced Ca2+ influx via TRPC6 and improves EC migration. p85α is a novel target to promote EC migration and arterial healing after injury. Abstract: Activation of phosphatidylinositol 3-kinase (PI3K) by lipid oxidation products, including lysophosphatidylcholine (lysoPC), increases the externalization of canonical transient receptor potential 6 (TRPC6) channels leading to a subsequent increase in intracellular calcium that contributes to cytoskeletal changes which inhibit endothelial cell (EC) migration in vitro and impair EC healing of arterial injuries in vivo. The PI3K p110α and p110δ catalytic subunit isoforms regulate lysoPC-induced TRPC6 externalization in vitro, but have many other functions. The goal of the current study is to identify the PI3K regulatory subunit isoform involved in TRPC6 externalization to potentially identify a more specific treatment regimen to improve EC migration and arterial healing, while minimizing off-target effects. Decreasing the p85α regulatory subunit isoform protein levels, but not the p85β and p55γ regulatory subunit isoforms, with small interfering RNA inhibits lysoPC-induced translocation of the PI3K catalytic subunit to the plasma membrane, dramatically decreased phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3) production and TRPC6 externalization, and significantly improves EC migration in the presence of lysoPC. These results identify the important and specific role of p85α in controlling translocation of PI3K from the cytosol to the plasma membrane and PI3K-mediated TRPC externalization by oxidized lipids. Current PI3K inhibitors block the catalytic subunit, but our data suggest that the regulatory subunit is a novel therapeutic target to promote EC migration and healing after arterial injuries that occur with angioplasty. Graphical abstract: Image, graphical abstract