PI(4,5)P is a master regulator for Ca-triggered vesicle exocytosis.

Substantial evidence indicates that phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P] is a plasma membrane phospholipid essential for Ca-dependent vesicle exocytosis. Ca-triggered vesicle exocytosis is a well-organized multiple-step membrane process including vesicle docking, priming, and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent fusion. A subset of vesicles are docked on high concentration plasma membrane PI(4,5)P microdomains that preferentially undergo exocytosis upon Ca-stimulation in neuroendocrine cells. PI(4,5)P microdomains also mediate plasma membrane SNARE proteins syntaxin-1 and SNAP-25 partitioning and clustering through electrostatic interactions. PI(4,5)P recruits and activates SNARE regulatory proteins such as calcium-dependent activator protein for secretion (CAPS, aka CADPS), mammalian uncoordinated-13 (Munc13), and synaptotagmin-1, which play pivotal roles in the priming and fusion steps of vesicle exocytosis. In this review, we discuss how PI(4,5)P controls each step of vesicle exocytosis through PI(4,5)P-binding effector proteins.