Recent advances in understanding phosphoinositide signaling in the nervous system

Abstract

Polyphosphoinositides (PPIn) are essential signaling phospholipids that make remarkable contributions to the identity of all cellular membranes and signaling cascades in mammalian cells. They exert regulatory control over membrane homeostasis via selective interactions with cellular proteins at the membrane-cytoplasm interface. This review article briefly summarizes our current understanding of the key roles that PPIn play in orchestrating and regulating crucial electrical and chemical signaling events in mammalian neurons and the significant neuro-pathophysiological conditions that arise following alterations in their metabolism.

Keywords: Endoplasmic reticulum; Ion channel; Membrane contact site; Neuron; Phosphatidylinositol; Phosphoinositide; Phospholipase C; Phospholipids; Plasma membrane; Polyphosphoinositide; Voltage gated Ca2+ channel; Voltage gated K+ channel.

Figure 1.. Phosphoinositide metabolism and biogenesis.

( A) Phosphoinositide metabolism. Hypothetical equilibrium reaction involving four polyphosphoinositide (PPIn) species at the membrane–cytosol interface. The basic structure of the parent PPIn, phosphatidylinositol (PtdIns), forms the substrate for subsequent PPIn species. Red labels represent gene names of lipid kinases that catalyze the addition of phosphate groups (phosphorylate) at specific positions of the inositol ring. Blue labels represent gene names of lipid phosphatases that remove phosphate groups (dephosphorylate) at specific positions of the inositol ring. ( B) Phosphoinositide biogenesis. Diagram summarizing the major PPIn lipid kinase and phosphatase reaction pathways. Red and blue labels are the gene names of enzymes capable of catalyzing each reaction. Gene names with question marks (?) represent enzymes with some uncertainty surrounding their ability to catalyze a specific reaction. Dashed arrows represent the major cellular roles for each individual PPIn. Colored circles represent the approximate cellular locations of each PPIn species. ER, endoplasmic reticulum; PKC, protein kinase C; PTEN, phosphatase and tensin homolog.

Figure 2.. Phosphoinositide zip code.

Cellular distribution of polyphosphoinositide (PPIn) species and metabolizing enzymes. Diagram depicting the signature distribution of each PPIn species and approximate location of enzymes regulating each species. Blue and red labels represent PPIn phosphatases and PPIn kinases, respectively. E.E., early endosome; ER, endoplasmic reticulum; PM, plasma membrane; PtdIns, phosphatidylinositol.

Figure 3.. Roles for polyphosphoinositides (PPIn) in the nervous system in health and disease.

( A) PtdIns(4,5) P ₂-dependent events. Critical events regulated by plasma membrane (PM) PtdIns(4,5) P ₂ within the nervous system. (i) Four families of ion channels that require PtdIns(4,5) P ₂ as a co-factor for full function. (ii) PtdIns(4,5) P ₂ is the critical precursor for generation of IP ₃-mediated Ca ²⁺ release and protein kinase C (PKC)-mediated phosphorylation. Binding of ligand (1) releases the heterotrimeric G-protein G _q (2) to activate phospholipase C (PLC), which subsequently hydrolyses PM PtdIns(4,5) P ₂ into membrane-bound DAG and soluble IP ₃ (3). DAG then can recruit PKC to phosphorylate protein targets (4) while IP ₃ binds to the IP ₃R on endoplasmic reticulum (ER) membranes to initiate Ca ²⁺ releases into the cytoplasm (5). (iii) Critical involvement of PtdIns(4,5) P ₂ in neurotransmitter release. During calcium-regulated synaptic vesicle release, PtdIns(4,5) P ₂ is required to attract many proteins to the PM active zone for docking and fusion. After fusion, the vesicle membrane is recovered via the clathrin adapter protein AP2 to form clathrin-coated pits (CCP), before dynamin-dependent membrane scission occurs during the final stages of endocytosis. ( B) PPIn deficiency in the nervous system. Diseases and cellular consequences for altered PPIn metabolism in the central (red box) and peripheral (blue box) nervous systems. CCP, clathrin coated pit; GPCR, G protein–coupled receptor; PtdIns, phosphatidylinositol.