Phosphoinositides in neuroexocytosis and neuronal diseases

Phosphoinositides (PIs) are a family of phospholipids derived from phosphatidylinositol (PtdIns), whose location, synthesis, and degradation depend on specific PI kinases and phosphatases. PIs have emerged as fundamental regulators of secretory processes, such as neurotransmitter release, hormone secretion, and histamine release in allergic responses. In neurons and neuroendocrine cells, regulated secretion requires the calcium-dependent fusion of transmitter-containing vesicles with the plasma membrane. The role played by PIs in exocytosis is best exemplified by the Ca²⁺-dependent binding of vesicular Synaptotagmin1 to the plasma membrane PtdIns(4,5)P₂, and the recently demonstrated role of PtdIns(4,5)P₂ in the mobilization of secretory vesicles to the plasma membrane. New evidence has also recently emerged of an alternative PI pathway that can control exocytosis positively (via PtdIn3P) or negatively (via PtdIns(3,5)P₂). However, the positive or negative effectors for these pathways remain to be established. Reducing PtdIns(3,5)P₂ potentiates neuroexocytosis but leads to neuronal degeneration and has been linked to certain forms of Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. The goal of this review is to describe the role of PIs in neuroexocytosis and explore the current hypotheses linking these effects to human diseases.