The Neuroplastin adhesion molecules: key regulators of neuronal plasticity and synaptic function

Abstract

The Neuroplastins Np65 and Np55 are neuronal and synapseenriched immunoglobulin superfamily molecules that play important roles in a number of key neuronal and synaptic functions including, for Np65, cell adhesion. In this review we focus on the physiological roles of the Neuroplastins in promoting neurite outgrowth, regulating the structure and function of both inhibitory and excitatory synapses in brain, and in neuronal and synaptic plasticity. We discuss the underlying molecular and cellular mechanisms by which the Neuroplastins exert their physiological effects and how these are dependent upon the structural features of Np65 and Np55, which enable them to bind to a diverse range of protein partners. In turn this enables the Neuroplastins to interact with a number of key neuronal signalling cascades. These include: binding to and activation of the fibroblast growth factor receptor; Np65 trans-homophilic binding leading to activation of p38 MAPK and internalization of glutamate (GluR1) receptor subunits; acting as accessory proteins for monocarboxylate transporters, thus affecting neuronal energy supply, and binding to GABA A a1, 2 and 5 subunits, thus regulating the composition and localization of GABA A receptors. An emerging theme is the role of the Neuroplastins in regulating the trafficking and subcellular localization of specific binding partners. We also discuss the involvement of Neuroplastins in a number of pathophysiological conditions, including ischaemia, schizophrenia and breast cancer and the role of a single nucleotide polymorphism in the human Neuroplastin (NPTN) gene locus in impairment of cortical development and cognitive functions.

The balancing act of GABAergic synapse organizers

“…Thus, it appears that IgSF9 and IgSF9b both contribute to organizing inhibitory synapse development, and that this occurs through different molecular mechanisms in distinct neuron types. The IgSF protein neuroplastin-65, specifically expressed in the forebrain and enriched in postsynaptic density (PSD) fractions, has been shown to regulate LTP at hippocampal synapses [44]. Although neuroplastin-65 was initially recognized to regulate excitatory synapse development, recent reports suggest that it is also required for inhibitory synapse development [44].…”

Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

“…BSG is one of the most up-regulated genes in metastatic cancer cells (31) and has multiple functions (17,18). BSG and NPTN bind S100A9 and cyclophilins A and B and up-regulate the expression of matrix metalloproteinase (17,32) to promote cancer-cell metastasis.…”

“…Their long forms are expressed only in photoreceptors in the retina (26) and in neurons (27), respectively, suggesting that Xkr8 is complexed with the short form of BSG or NPTN in most cells. EMB is a member of the BSG family (18), but unlike BSG and NPTN it could not chaperone Xkr8. The transmembrane region is highly conserved among BSG, NPTN, and EMB (58.3-62.5% identical) (Fig.…”

“…We purified the Xkr8 complex from membrane fractions and determined that it associated with basigin (BSG) or neuroplastin (NPTN) (17,18). We found that BSG or NPTN is required for Xkr8's function as a caspase-dependent phospholipid scramblase.…”

Pharmacotherapy of cognition in schizophrenia

“…Although cognition is markedly abnormal in many with schizophrenia, the core mechanism of synaptic neurotransmission, excitation and inhibition produced by neurotransmitters and growth factors, operating within neurocircuits, and regional specialization, appear to be similar in rodents, primates,and man. This has facilitated the development of animal models of CIS which manifest many of the abnormalities reported in schizophrenia, including decreased cortical dopaminergic activity [44], increased striatal dopaminergic activity [8 ], decreased cholinergic function [46,47], deficient GABAergic inhibition of pyramidal neurons [5], immature hippocampi [53], abnormalities in the large number of proteins that participate in synaptic spine development, maintenance, and activity-dependent plasticity [54,55], and abnormalities in connectivity producing disrupted theta and other organized oscillations [56,57]. This ever expanding preclinical CIS literature has been extensively reviewed [8 ,15, 44,58,59].…”