Phosphoinositides in Neuroexocytosis and Neuronal Diseases

Abstract

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.

Emerging evidence for the modulation of exocytosis by signalling lipids

“…) , being recruited in secretory sites by intracellular calcium elevations during cell stimulation . Today, these initial studies have been supported by recent studies proving that PIP2 coordinates the translocation of secretory vesicles to their docking sites on the plasma membrane in a Cdc42‐dependent manner . In that way, forms clusters that, in addition to nucleation of the formation of F‐actin bundles, also interact with SNARE proteins , and in consequence act as a beacon for vesicle guidance to active secretory sites (Fig.…”

A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability

“…Furthermore, reduction of phosphatidylinositol 3,5-bisphosphate potentiates neuroexocytosis and leads to neuronal degeneration, a mechanism that has been linked to certain forms of Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. 30 In short, the strategy of combining field investigation in highly inbred areas of Brazil, searching for of clusters of genetic disorders, with a state-of-art molecular approach proved once again to be successful. Using this approach, our group has recently identified, in a neighboring community, MED25 as another gene associated with autosomal recessive ID.…”

Metabolic profiling of zebrafish (Danio rerio) embryos by NMR spectroscopy reveals multifaceted toxicity of β-methylamino-L-alanine (BMAA)

“…Numerous, previous studies demonstrate a role of inositol-containing lipids (as substrates for kinases/phosphatatases) in various key regulatory functions in the brain 47 including neural development. And moreover, emerging evidence suggests a contribution to both neuroexcitatory processes 58 , and neurodegeneration 59 . Taken together with the other diverse roles of lipids in cell membrane integrity, and myelination, observed effects on lipid biosynthesis (as revealed by the present integrated metabolomics approach) point to a previously unrecognized role of these metabolic pathways with respect to the apparently multifaceted contribution of BMAA to neurodegeneration.…”