Polyphosphoinositol lipids: Under‐PPInning synaptic function in health and disease

Abstract

Phosphoinositides (PPIn) form a unique family of lipids derived by phosphorylation of the parent compound, phosphatidylinositol. Despite being minor constituents of synaptic membranes, these lipids have exceptionally high rates of metabolic turnover and are involved with myriad aspects of pre- and post-synaptic function, from the control of the synaptic vesicle cycle to postsynaptic excitability. In this review, we outline the main synaptic processes known to be regulated by these molecules, focusing mainly but not exclusively on the major species phosphatidylinositol 4-phosphate and phosphatidylinositol (4,5)-bisphosphate. Furthermore, we discuss the enzymes responsible for their synthesis and degradation, with a view to exploring how the activity-dependent control of their enzymatic action can lead to the precise regulation of PPIn levels at the nerve terminal. Also, the modulation of synaptic PPIn turnover by drugs used for the treatment of bipolar disorder is discussed. We propose that the modulation of PPIn levels may act as a central mechanism to coordinate the cascade of synaptic events leading to neurotransmission.

An Introduction to Phosphoinositides

“…Because of their palmitoylation, Type II PI4Ks are tightly membrane-bound proteins, although a significant larger fraction of PI4KIIb than PI4KIIa is cytosolic. PI4KIIa was cloned from membranes of large dense core vesicles in neurons and although it has been suggested that both isoforms may be associated with synaptic vesicles, it seems that the main isoform in these vesicles is PI4KIIa (Hammond and Schiavo 2007). Both PI4KIIa and PI4KIIb localised to intracellular membranes, mostly TGN and endosomes (Balla and Balla 2006) but they are also present in compartments that contain the AP-3 adaptor complex and in GLUT4-containing vesicles (D'Angelo et al 2008).…”

“…In this respect, it must be noted that the pool of PtdIns4P to be converted into PtdIns(4,5)P 2 can be either delivered to the plasma membrane by membrane carriers derived from the Golgi complex and from recycling organelles or it can be produced locally at the plasma membrane by PI4Ks (Di Paolo and De Camilli 2006). For instance, it seems that de novo synthesis of PtdIns4P, followed by action of PIP5K, is required for generation of synaptic PtdIns(4,5)P 2 rather than stored PtdIns4P (Hammond and Schiavo 2007). Synthesis of this PI, therefore, represents a key step in modulation of the levels of PtdIns(4,5)P 2 .…”

Lipid dynamics at dendritic spines

“…Despite phosphoinositides (PIPs) are minor components of synaptic membranes, their exceptional high rate of metabolic turnover and their compartmentalization make them key players in postsynaptic excitability (Hammond and Schiavo, 2007). The presence at dendritic spines of the enzymes that interconvert different PIPs supports a relevant role for these lipids in the dynamics of these structures.…”

Phosphoinositide turnover in Toll-like receptor signaling and trafficking

“…PI(4,5)P2 is necessary for synaptic vesicle exocytosis, and its production by PIP5Kγ and hydrolysis by synaptojanin also participate in clathrin-mediated endocytosis (20-22). Various synaptic proteins are recruited to the presynaptic membranes through specific interactions with PI(4,5)P2.…”