Processing of Neuregulin-1 by Neuropsin Regulates GABAergic Neuron to Control Neural Plasticity of the Mouse Hippocampus

Abstract

Protease-mediated signaling is an important modulator of the nervous system. However, identifying the specific signaling substrates of such proteases is limited by the rapidity with which intermediate substrate forms are cleaved and released. Here, a screening method to detect noncleaved enzyme-bound forms was developed and used to identify a novel neuropsin/neuregulin-1 (NRG-1) proteolytic signaling system, which is specifically localized in the microdomain of synaptic cleft, in the mouse hippocampus. The extracellular protease, neuropsin, cleaved mature NRG-1 (comprising the extracellular domain of the NRG-1) at three newly identified sites to remove the heparin-binding domain of NRG-1. This released the ligand moiety from the matrix-glycosaminoglycan pool and enabled it to trigger the phosphorylation of NRG-1 receptor, p185 (ErbB4). Proteolysis of mature NRG-1 by neuropsin led to colocalization of the processed NRG-1 with ErbB4 in parvalbumin-positive hippocampal interneurons and consequent phosphorylation of tyrosine residues of proteins in the cells. Moreover, neuropsin knock-out mice exhibited impairments in Schaffer collateral early phase long-term potentiation, and application of the recombinant NRG-1 lacking heparin-binding activity reversed the effects through the activation of ErbB4 and GABA A receptors. Thus, ErbB4 signaling induced by neuropsin-dependent processing of NRG-1 contributes to the modulation of synaptic plasticity via regulation of GABAergic transmission. This signaling system may be involved in human cognition and mental disorders, such as schizophrenia and bipolar disorder, by its dysfunction.

Kallikrein‐8 inhibition attenuates Alzheimer's disease pathology in mice

“…Kallikrein-8 (KLK8, also known as neuropsin) is a synaptic plasticity-modulating extracellular serine protease [1,2]. Among other substrates KLK8 cleaves the ephrin receptor B2 (EPHB2) and thereby induces various signaling cascades.…”

Unleashing the therapeutic potential of human kallikrein-related serine proteases

“…Stress-induced KLK8 activity leads to increased cleavage of ephrin type B receptor 2 (EPHB2) on the surface of amygdala neurons, promoting anxiety-like behaviour in mice 161 (TABLE 1). Moreover, KLK8 was recently linked to schizophrenia, as it directly targets the key schizophrenia-related molecule neuregulin 1 (NRG1) 162 . NRG1 and its receptor tyrosine-protein kinase, ERBB4, have important roles in regulating hippocampal and frontal cortical pyramidal neurons, and abnormal expression of NRG1 isoforms is associated with increased risk of developing schizophrenia 163 .…”

“…NRG1 and its receptor tyrosine-protein kinase, ERBB4, have important roles in regulating hippocampal and frontal cortical pyramidal neurons, and abnormal expression of NRG1 isoforms is associated with increased risk of developing schizophrenia 163 . KLK8-mediated cleavage of NRG1 results in the release of the NRG1 EGF-like domain, which, in turn, activates ERBB4 receptors and leads to an impairment of γ-aminobutyric acid (GABA) ergic inhibitory transmission and excessive postsynaptic excitation 162 (FIG. 6a).…”

“…In the hippocampus, KLK8 has an important role in regulating γ-aminobutyric acid (GABA)ergic transmission. In wild-type mice, KLK8 cleaves the heparin-binding domain of neuregulin 1 (NRG1) and releases a functional epidermal growth factor (EGF)-like domain of NRG1 from the matrix component heparan sulfate proteoglycan (HSPG), which acts as a ligand moiety that binds and activates tyrosine-protein kinase ERBB4 receptors on parvalbumin-positive basket interneurons 162 . Basket interneurons form inhibitory synapses on the somata of pyramidal cells and control their output via GABAergic transmission.…”

Does extracellular proteolysis control mammalian cognition?

“…Exodomain release Ligand release 22 kDa fragment released from agrin by neurotrypsin proteolysis binds to Na + /K + -ATPase subunit (Hilgenberg et al, 2006). Functional domain of neuregulin-1 type I cleaved by neuropsin acts as ligand of ErbB4 receptor (Tamura et al, 2012).…”