Review
Neuropsin—A possible modulator of synaptic plasticity

https://doi.org/10.1016/j.jchemneu.2011.05.014Get rights and content

Abstract

Accumulating evidence has suggested pivotal roles for neural proteases in development, maturation, aging, and cognitive functions. Among such proteases, neuropsin, a kallikrein gene-related (KLK) endoprotease, appears to have a significant plasticity function that has been analyzed primarily in the hippocampal Schaffer-collateral pathway. In this article, after reviewing the general features of neuropsin, its role in Schaffer-collateral synaptic plasticity is discussed in some detail. Enzymatically active neuropsin is necessary to establish the early phase of long-term potentiation (LTP). This type of LTP, which can be elicited by rather weak tetanic stimulation, is significant in synaptic late association between two independent hippocampal synapses. Neuropsin deficiency completely impaired the early phase of LTP, leading to the absence of late associativity. Associations between early and persistent-LTP synapses may be related to mammalian working memory and consequently integration in learning and memory.

Highlights

► Current studies have suggested pivotal roles for neural proteases in development, maturation, aging, and cognition. ► In the present review article, possible neural function of neuropsin, a serine protease, was focused, and importance in early phase of LTP was descried. ► The involvement of neuropsin in the single synaptic function leads to relate to synaptic late association between two independent hippocampal synapses. ► This hypothetical synaptic associations may be related to mammalian working memory and consequently integration in learning and memory.

Introduction

The concept that macromolecular cleavage or shedding in the synaptic cleft mediates intracellular signals involved in synaptic functions has become increasing familiar in the field of neuroscience. Reverse-transcription polymerase chain reaction for mouse hippocampal mRNAs using primers designed based on the consensus catalytic domain of secretory serine proteases screened out several protease genes including kallikrein-related endopeptidase gene1 (KLK) 8, encoding neuropsin (alternative terminology: TADG-14, bsp1, or ovasin); KLK6, encoding neurosin (alternative terminology: zyme or protease M); and tissue plasminogen activator (tPA)2 (Chen et al., 1995). Currently, accumulating evidence supports pivotal roles of these neural proteases not only in development, maturation, and aging, but also in higher nervous functions such as cognition. Here, we review the general features of neuropsin and discuss its possible roles in synaptic plasticity, particularly in the hippocampal region.

Section snippets

Expression of KLK8 in the brain

Under non-pathological conditions, KLK8 (neuropsin gene) is localized mainly to the principal neurons of the limbic brain. In situ hybridization histochemistry for KLK8 demonstrated dense signals in pyramidal neurons of the hippocampal CA1–3 subfields and magnocellular neurons of the lateral/basolateral amygdaloid nucleus (Chen et al., 1995). Significant signals were also observed in pyramidal neurons of the cerebral cortex including prefrontal, cingulate and entorhinal regions.

Initial

Evolution of KLK8

KLK8 is a member of the KLK multigene family, which is located on a single chromosome, 7B2 in mouse and 19q13.4 in human. Although basic proteolytic enzymes emerged very early in the most primitive organisms, the evolution of KLK-family genes, including KLK8, is a recent phenomenon. In silico investigation of the KLK family indicated that there was no KLK in bird (chicken) or amphibian (African clawed frog) species, but orthologues of KLK5–15 were found in marsupial species (opossum) (Elliott

Protein structure and zymogen activation of neuropsin

All proteases in the KLK family are homologous with (chymo)trypsin and have well-conserved amino acid sequences and structures, particularly in the catalytic domain (Kishi et al., 1999, Bernett et al., 2002, Debela et al., 2006). The crystal structure of (type 1) neuropsin contains a serine protease fold that exhibits chimeric features of trypsin and γ-NGF, both of which are part of the S1 family (clan SA) of serine proteases according to the Melops classification (Kishi et al., 1999, Bernett

Potential substrates and receptors of neuropsin

Since consensus sequences cleaved by neuropsin are not yet fully established, screening target macromolecules on the basis of such substrate specificity is difficult. However, some extracellular domains of transmembrane and extracellular matrix proteins have been identified by in vitro assays using randomly selected native or recombinant proteins. Generally, specific cleavage sites are present in or around the fibronectin domain of fibronectin (Shimizu et al., 1998), L1-cell adhesion molecule

Involvement of neuropsin on the early phase of synaptic plasticity, late associativity, and behavioral memory

Hippocampal early phase LTP elicited by a weak (one 100-Hz) tetanic stimulus normally fades within 90 min. This form of LTP is independent of protein synthesis. In contrast, late-phase LTP elicited by a strong (four 100-Hz) stimulus lasts >180 min and requires new protein synthesis to persist, thus representing protein synthesis-dependent LTP. These two temporal phases of LTP occur independently to establish hyperefficacy in synaptic transmission and are regulated by different signaling systems (

Little overlap in plasticity roles among neural proteases

Although the cleavage/shedding of extracellular proteins by neural proteases has not yet been fully clarified, results obtained to date based on substrate specificities and differences in physiological responses indicate that each protease seems to have separate, non-redundant functions in plasticity. Neural proteases are known to be involved in LTP through the potential cleavage/shedding of cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins (Qian et al., 1993, Momota et

Perspectives

Neural activity-dependent extracellular proteolysis by proteases is a novel molecular mechanism that may relate to learning and memory for the acquisition and storage of newly acquired input in the hippocampus and probably also the prefrontal cortical regions. Physiological evidence suggests that a neuropsin-dependent process contributes to synaptic tagging in weakly stimulated synapses and the conversion of early to late-phase LTP on association with persistently potentiated synapses. Weak

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