RT Journal Article SR Electronic T1 Endosomal Phosphatidylinositol 3-Kinase Is Essential for Canonical GPCR Signaling JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 65 OP 73 DO 10.1124/mol.116.106252 VO 91 IS 1 A1 Yasunori Uchida A1 Florentine U. Rutaganira A1 Damien Jullié A1 Kevan M. Shokat A1 Mark von Zastrow YR 2017 UL http://molpharm.aspetjournals.org/content/91/1/65.abstract AB 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 3-kinase (Vps34), which is 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, which is in accord with the established role of recycling in GPCR resensitization. In addition, Vps34 inhibition also attenuates the short-term cAMP response, and its effect begins several minutes after initial agonist application. These results establish Vps34 as an essential determinant of both short-term and long-term canonical GPCR signaling, and support the potential utility of the endosomal system as a druggable target for signaling.