Cleavage of the NR2B Subunit Amino Terminus of N-Methyl-d-aspartate (NMDA) Receptor by Tissue Plasminogen Activator

Ng, Kay-Siong; Leung, How-Wing; Wong, Peter T.-H.; Low, Chian-Ming

doi:10.1074/jbc.m112.374397

Cited by 21 publications

(9 citation statements)

References 59 publications

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“…This cleavage can occur at two sites: lysine 317 on GluN2A, which relieves Zn 2+ inhibition and thereby increases NMDAR function, 37 and arginine 67 on GluN2B, which increases sensitivity of the NMDA receptor to glycine. 38 …”

Section: Discussionmentioning

confidence: 99%

Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors

et al. 2016

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N-methyl-d-aspartate receptors (NMDARs) are ion channels whose synaptic versus extrasynaptic localization critically influences their functions. This distribution of NMDARs is highly dependent on their lateral diffusion at the cell membrane. Each obligatory subunit of NMDARs (GluN1 and GluN2) contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). To date, the roles and dynamics of the NTD of the GluN1 subunit in NMDAR allosteric signaling remain poorly understood. Using single nanoparticle tracking in mouse neurons, we demonstrate that the extracellular neuronal protease tissue-type plasminogen activator (tPA), well known to have a role in the synaptic plasticity and neuronal survival, leads to a selective increase of the surface dynamics and subsequent diffusion of extrasynaptic NMDARs. This process explains the previously reported ability of tPA to promote NMDAR-mediated calcium influx. In parallel, we developed a monoclonal antibody capable of specifically blocking the interaction of tPA with the NTD of the GluN1 subunit of NMDAR. Using this original approach, we demonstrate that the tPA binds the NTD of the GluN1 subunit at a lysine in position 178. Accordingly, when applied to mouse neurons, our selected antibody (named Glunomab) leads to a selective reduction of the tPA-mediated surface dynamics of extrasynaptic NMDARs, subsequent signaling and neurotoxicity, both in vitro and in vivo. Altogether, we demonstrate that the tPA is a ligand of the NTD of the obligatory GluN1 subunit of NMDAR acting as a modulator of their dynamic distribution at the neuronal surface and subsequent signaling.

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Section: Discussionmentioning

confidence: 99%

Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors

et al. 2016

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“…The NR2B subunit of the NMDA receptor is also subject to proteolytic regulation by tissue plasminogen activator (tPA) [40]. A truncated NR2B protein, designed based on the predicted site of tPA cleavage was unaffected in terms of glutamate activation but exhibited reduced propensity to be inhibited by the antagonist ifenprodil and displayed an increased affinity for glycine.…”

Section: Regulation Of Ion Channels Activities By Proteolysismentioning

confidence: 99%

Differential regulation of ion channels function by proteolysis

Wang¹,

Yule²

2018

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Ion channels are pore-forming protein complexes in membranes that play essential roles in a diverse array of biological activities. Ion channel activity is strictly regulated at multiple levels and by numerous cellular events to selectively activate downstream effectors involved in specific biological activities. For example, ions, binding proteins, nucleotides, phosphorylation, the redox state, channel subunit composition have all been shown to regulate channel activity and subsequently allow channels to participate in distinct cellular events. While these forms of modulation are well documented and have been extensively reviewed, in this article, we will first review and summarize channel proteolysis as a novel and quite widespread mechanism for altering channel activity. We will then highlight the recent findings demonstrating that proteolysis profoundly alters Inositol 1,4,5 trisphosphate receptor activity, and then discuss its potential functional ramifications in various developmental and pathological conditions.

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“…Results from the Vivien group suggest that tPA may act by interacting with the GluN1 subunit of NMDA receptors, particularly in GluN2D-containing receptors (Benchenane et al, 2007 ; Macrez et al, 2010 ; Obiang et al, 2012 ). Other results suggest that tPA modulates NMDA signaling through GluN2B subunits (Pawlak et al, 2005a ; Norris and Strickland, 2007 ; Noel et al, 2011 ; Ng et al, 2012 ) or by a mechanism involving LRP (Martin et al, 2008 ; Samson et al, 2008 ). The importance of LRP in tPA-mediated neuronal plasticity was also reported in an earlier study on LTP (Zhuo et al, 2000 ).…”

Section: Effects Of Tpa and Neuroserpin On Neuronal Plasticitymentioning

confidence: 99%

Physiological and pathological roles of tissue plasminogen activator and its inhibitor neuroserpin in the nervous system

Lee

Tsang

Birch

2015

Front. Cell. Neurosci.

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Although its roles in the vascular space are most well-known, tissue plasminogen activator (tPA) is widely expressed in the developing and adult nervous system, where its activity is believed to be regulated by neuroserpin, a predominantly brain-specific member of the serpin family of protease inhibitors. In the normal physiological state, tPA has been shown to play roles in the development and plasticity of the nervous system. Ischemic damage, however, may lead to excess tPA activity in the brain and this is believed to contribute to neurodegeneration. In this article, we briefly review the physiological and pathological roles of tPA in the nervous system, which includes neuronal migration, axonal growth, synaptic plasticity, neuroprotection and neurodegeneration, as well as a contribution to neurological disease. We summarize tPA's multiple mechanisms of action and also highlight the contributions of the inhibitor neuroserpin to these processes.

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Cleavage of the NR2B Subunit Amino Terminus of N-Methyl-d-aspartate (NMDA) Receptor by Tissue Plasminogen Activator

Cited by 21 publications

References 59 publications

Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors

Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors

Differential regulation of ion channels function by proteolysis

Physiological and pathological roles of tissue plasminogen activator and its inhibitor neuroserpin in the nervous system

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