Activity-Dependent Shedding of the NMDA Receptor Glycine Binding Site by Matrix Metalloproteinase 3: A PUTATIVE Mechanism of Postsynaptic Plasticity

Pauly, Thorsten; Ratliff, Miriam; Pietrowski, Eweline; Neugebauer, R; Schlicksupp, Andrea; Kirsch, Joachim; Kuhse, Jochen

doi:10.1371/journal.pone.0002681

Cited by 43 publications

(47 citation statements)

References 36 publications

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“…However, Western blot analysis of pro-and mature BDNF levels were not found to be prominently altered in MMP-3 −/− cerebella (data not shown), indicating that BDNF might not be the major MMP-3 substrate responsible for the observed cerebellar phenotype in MMP-3 −/− mice. Other substrates out of the very broad MMP-3 degradome and known to be involved in parallel fiber outgrowth and/or GC migration are vitronectin, NMDA receptors, and MMP-9 [1,5,7,38,[45][46][47]. Although MMP-9 shows a resembling mRNA and protein expression profile in the developing cerebellum and modulates GC exit from the EGL, MMP-9 deficiency or inhibition is known to affect GC apoptosis and reduce parallel fiber outgrowth, processes which were not affected or opposite in MMP-3 −/− animals [5,7].…”

Section: Discussionmentioning

confidence: 99%

An Aberrant Cerebellar Development in Mice Lacking Matrix Metalloproteinase-3

et al. 2011

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Cell-cell and cell-matrix interactions are necessary for neuronal patterning and brain wiring during development. Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of remodelling the pericellular environment and regulating signaling pathways through cleavage of a large degradome. MMPs have been suggested to affect cerebellar development, but the specific role of different MMPs in cerebellar morphogenesis remains unclear. Here, we report a role for MMP-3 in the histogenesis of the mouse cerebellar cortex. MMP-3 expression peaks during the second week of postnatal cerebellar development and is most prominently observed in Purkinje cells (PCs). In MMP-3 deficient (MMP-3(-/-)) mice, a protracted granule cell (GC) tangential migration and a delayed GC radial migration results in a thicker and persistent external granular layer, a retarded arrival of GCs in the inner granular layer, and a delayed GABAergic interneuron migration. Importantly, these neuronal migration anomalies, as well as the consequent disturbed synaptogenesis on PCs, seem to be caused by an abnormal PC dendritogenesis, which results in reduced PC dendritic trees in the adult cerebellum. Of note, these developmental and adult cerebellar defects might contribute to the aberrant motor phenotype observed in MMP-3(-/-) mice and suggest an involvement of MMP-3 in mouse cerebellar development.

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Section: Discussionmentioning

confidence: 99%

An Aberrant Cerebellar Development in Mice Lacking Matrix Metalloproteinase-3

et al. 2011

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“…Recently, several studies have indicated that under special conditions, such as inflammatory or degenerative diseases of the central nervous system, matrix metalloproteinases cleave the NR1a subunit at the extracellular NH 2 -terminal domain and modify NMDA receptor function (36,37). Tissue-type plasminogen activator is also known to bind to and then cleave the ATD of the NR1 subunit at arginine 260, which serves as a necessary step to enhance NMDA receptor signaling in neurons (38,39).…”

Section: Nr2a Atd Contains An Er Retentionmentioning

confidence: 99%

An Endoplasmic Reticulum Retention Signal Located in the Extracellular Amino-terminal Domain of the NR2A Subunit of N-Methyl-d-aspartate Receptors

Qiu

Zhang

Cao

et al. 2009

Journal of Biological Chemistry

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N-Methyl-D-aspartate (NMDA) receptors play critical roles in complex brain functions as well as pathogenesis of neurodegenerative diseases. There are many NMDA isoforms and subunit types that, together with subtype-specific assembly, give rise to significant functional heterogeneity of NMDA receptors. Conventional NMDA receptors are obligatory heterotetramers composed of two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits. When individually expressed in heterogeneous cells, most of the NR1 splice variants and the NR2 subunits remain in the endoplasmic reticulum (ER) and do not form homomeric channels. The mechanisms underlying NMDA receptor trafficking and functional expression remain uncertain. Using truncated and chimeric NMDA receptor subunits expressed in heterogeneous cells and hippocampal neurons, together with immunostaining, biochemical, and functional analyses, we found that the NR2A amino-terminal domain (ATD) contains an ER retention signal, which can be specifically masked by the NR1a ATD. Interestingly, no such signal was found in the ATD of the NR2B subunit. We further identified the A2 segment of the NR2A ATD to be the primary determinant of ER retention. These findings indicate that NR2A-containing NMDA receptors may undergo a different ER quality control process from NR2B-containing NMDA receptors. Ionotropic glutamate receptors (iGluRs)2 mediate most of the excitatory neurotransmission in the central nervous system. They play key roles in complex brain functions as well as in the pathogenesis of neurodegenerative diseases. Based on pharmacological properties and sequence similarities, iGluRs can be grouped into three major subtypes: GluR1 to -4 subunits form ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, GluR5 to -7 and KA1 and -2 subunits make up kainate receptors, and NR1 together with NR2A to -D subunits comprise the NMDA receptors (1). All iGluR subunits share a unique membrane topology with a large extracellular NH 2 -terminal domain, three transmembrane segments (TM1 (transmembrane domain 1), TM3, and TM4), a P-loop region, and a cytoplasmic COOH terminus (2, 3). Based on the sequence homology to bacterial periplasmic binding proteins, the NH 2 -terminal domain of iGluRs can be divided into two domains in tandem: the amino-terminal domain (ATD), which includes the first 400 or so amino acids (4), and the following S1 domain preceding TM1, which forms the ligand-binding domain together with the extracellular loop between TM3 and TM4 (S2 domain) (5, 6).Among iGluRs, NMDA receptors are special in that conventional NMDA receptors are obligatory tetrameric membrane proteins composed of two glycine-binding NR1 and two glutamate-binding NR2 subunits. The NR1 subunit is essential for the formation of functional NMDA receptor channel, whereas the NR2 subunit modifies channel properties, such as current kinetics and channel conductance (1). The major NR1 splice variant and the NR2 subunits are retained in the ER when expressed alone in heterogeneous cells. On...

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“…Interestingly, it has been reported that NMDAR has been found to associate with metabotropic dopamine receptors [149]. There is also a possibility that Ca 2+ flux-independent metabotropic-like NMDAR function could be the result of proteolytic cleavage, as that already reported for NMDAR subunit GluN1 [150], that occurs to other membrane molecules [151]. In addition, GluN2C subunit-mediated IC signaling, found highly expressed in most transcriptome analysis of astrocytes, but that has been poorly studied, could be involved.…”

Section: Insights Regarding Astrocytic Nmdarmentioning

confidence: 81%

NMDA Receptors in Astroglia: Chronology, Controversies, and Contradictions from a Complex Molecule

Balderas¹,

GonzálezHernández²

2018

Astrocyte - Physiology and Pathology

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The neurocentric theory dismissed for decades the role of glia in information handling within the central nervous system (CNS). Nevertheless, almost 3 decades ago, this started to change and today astrocytes are considered relevant players for this function. Astrocytes "listen" to neuronal communication, regulate it, and respond at the cellular and synctitial level. Ionotropic glutamate NMDA receptor (NMDAR) is critical in CNS. It mediates synaptic neuronal communication and it is involved in different mechanisms. However, NMDAR is also expressed by astrocytes, but its functional role in these cells has not been deeply investigated and has been a matter of debate in the last decades. In this chapter, we briefly outline NMDAR intracellular transduction pathways initiated by Ca 2+ flux. Then, we review chronologically NMDAR expression and function in astrocytes that have been a source of controversies and apparent contradictions. Finally, some insights are presented regarding NMDAR in astrocytes in the context of the tripartite synapse concept and the recently described Ca 2+ fluxindependent metabotropic-like NMDAR function in astrocytes. Given the complex molecular nature of NMDAR, its critical role, and the relevance of astrocytes, the study of astrocytic NMDAR promises to provide further understanding of CNS physiology and pathology.

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Activity-Dependent Shedding of the NMDA Receptor Glycine Binding Site by Matrix Metalloproteinase 3: A PUTATIVE Mechanism of Postsynaptic Plasticity

Cited by 43 publications

References 36 publications

An Aberrant Cerebellar Development in Mice Lacking Matrix Metalloproteinase-3

An Aberrant Cerebellar Development in Mice Lacking Matrix Metalloproteinase-3

An Endoplasmic Reticulum Retention Signal Located in the Extracellular Amino-terminal Domain of the NR2A Subunit of N-Methyl-d-aspartate Receptors

NMDA Receptors in Astroglia: Chronology, Controversies, and Contradictions from a Complex Molecule

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