%0 Journal Article %A Yasunori Uchida %A Florentine U Rutaganira %A Damien Jullie %A Kevan M Shokat %A Mark von Zastrow %T Endosomal phosphatidylinositol 3-kinase is essential for canonical GPCR signaling %D 2016 %R 10.1124/mol.116.106252 %J Molecular Pharmacology %P mol.116.106252 %X G protein-coupled receptors (GPCRs), the largest family of signaling receptors, are critically regulated by endosomal trafficking, suggesting that endosomes might provide new strategies for manipulating GPCR signaling. Here we test this hypothesis by focusing on class III phosphatidylinositol (PI) 3-kinase or Vps34, an essential regulator of endosomal trafficking. We verify that Vps34 is required for recycling of the β2-adrenoceptor (β2AR), a prototypical GPCR, and then investigate the effects of Vps34 inhibition on the canonical cAMP response elicited by β2AR activation. Vps34 inhibition impairs the ability of cells to recover this response after prolonged activation, in accord with the established role of recycling in GPCR resensitization. In addition, Vps34 inhibition also attenuates the acute cAMP response, and its effect begins several minutes after initial agonist application. These results establish Vps34 as an essential determinant of both acute and long-term canonical GPCR signaling, and support the potential utility of the endosomal system as a druggable target for signaling. %U https://molpharm.aspetjournals.org/content/molpharm/early/2016/11/07/mol.116.106252.full.pdf