β-arrestin–dependent PI(4,5)P <sub>2</sub> synthesis boosts GPCR endocytosis
Seung‐Ryoung Jung, Yifei Jiang, Jong Bae Seo, Daniel T. Chiu, Bertil Hille, Duk‐Su Koh
Abstract
Significance Stimulation of protease-activated receptor 2 (PAR2) at the plasma membrane triggers a branching cascade of interrelated events in several cellular compartments. In one branch, the G protein G q couples to phospholipase C, and the membrane phosphoinositide lipids PI(4,5)P 2 and PI(4)P are depleted. In another branch, the receptor becomes desensitized by becoming phosphorylated, bound to β-arrestin, and internalized by clathrin-coated pits. This second branch needs PI(4,5)P 2 at several steps. We found that β-arrestin in complex with receptors stably binds to clathrin-coated pits and increases transient binding of the PI(4,5)P 2 synthetic enzyme PIP5K-Iγ. Then, this complex in clathrin-coated pits boosts the rate of PI(4,5)P 2 synthesis from Golgi and plasma membrane PI(4)P, so that PI(4,5)P 2 becomes elevated. The new PI(4,5)P 2 allows receptor internalization.