Dynamic control of neuroexocytosis by phosphoinositides in health and disease

Phosphoinositides are a group of phospholipids whose inositol headgroups can be phosphorylated at three distinct positions thereby generating seven different isotypes. The conversion between these lipid species depends on the activity of specific sets of phosphoinositide kinases and phosphatases whose targeting and activity is critical to establish the landscape of phosphoinositides on the cytosol-facing hemi-membrane of all organelles and plasmalemma. Phosphoinositides play pleiotropic roles ranging from signalling and membrane trafficking to modulation of ion channels and survival. In neurons and neurosecretory cells, whose main function is to communicate through the release of neurotransmitter, most of the work has focused on the role played by phosphatidylinositol (4,5) bisphosphate in controlling the mechanism underpinning neurotransmitter release through the fusion of secretory vesicles with the plasmalemma. Emerging evidence supports a multi-faceted regulation of neuroexocytosis by 3-phosphorylated phosphoinositides. In this review, we summarise the molecular mechanism by which these lipids control exocytosis and how minute changes in their metabolism can have devastating effects in the nervous system and lead to neurodegeneration.