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The Dichotomous Role of N-Methyl-D-Aspartate Receptors In Holmes AR, Castellino FJ, Balsara RD. The Dichotomous Role of N- methyl- D- Aspartate Receptors in Ischemic Stroke. J Cardiol and Cardiovasc Sciences (2018) 2(4): 23-32 Mini Review Article Open Access The Dichotomous Role of N- methyl- D- Aspartate Receptors in Ischemic Stroke Adam R. Holmes1, Francis J. Castellino1,2, Rashna D. Balsara1,2* 1W. M. Keck Center for Transgene Research, University of Notre Dame, Indiana 46556, USA 2Department of Chemistry and Biochemistry, University of Notre Dame, Indiana 46556, USA Article Info Abstract Article Notes Ischemia-­mediated­ glutamate­ elevation­ causes­ activation­ of­ the­ N-­methyl-­ Received: May 15, 2018 D-­aspartate­ receptor­ (NMDAR)­ and­ consequent­ excitotoxicity.­ This­ triggers­ Accepted: August 11, 2018 a­ cascade­ of­ pathological­ events,­ including­ aberrant­ NMDAR­ ion­ channel­ 2+ *Correspondence: kinetics,­ large­ neuronal­ Ca ­ influx,­ and­ activation­ of­ pro-­death­ signaling­ Dr. Rashna D. Balsara, Department of Chemistry and pathways.­ Previous­ studies­ have­ shown­ that­ functional­ outcomes­ of­ post-­ Biochemistry, University of Notre Dame, Indiana 46556, ischemia­are­influenced­by­the­type­of­GluN2­subunit­assembled­in­the­NMDAR­ USA; Telephone No: (574) 631- 2958; Fax No: (574) 631- (GluN2A,­GluN2B,­GluN2C,­or­GluN2D),­as­well­as­its­cellular­location.­GluN2A-­ 4048; Email: [email protected]. containing­ synaptic­ NMDAR’s­ activate­ pro-­survival­ pathways,­ whereas,­ © 2018 Balsara RD. This article is distributed under the terms of activation­of­GluN2B-­containing­extrasynaptic­NMDARs­results­in­cell­death.­ the Creative Commons Attribution 4.0 International License. However,­there­is­no­consensus omnium­on­the­individual­role­of­the­GluN2­ subunits­in­ischemia.­Published­studies­suggest­that­the­GluN2A,­GluN2B,­and­ Keywords: GluN2C­subunits­can­promote­either­neuronal­death­or­survival,­depending­ Ischemia on­the­experimental­model­employed­and­the­CNS­region­investigated.­In­this­ N- methyl- D- aspartate receptor mini-­review,­we­aim­to­succinctly­outline­the­mechanisms­that­underlie­the­ GluN2 subunits Calcium influx dichotomous­ role­ of­ the­ NMDAR­ in­ ischemic­ stroke­ and­ possible­ NMDAR-­ Synaptic directed­therapeutic­approaches. Extrasynaptic Signaling Introduction The N- methyl- D- aspartate receptor (NMDAR) is a ligand and voltage gated ionotropic neuroreceptor that is co- agonized by of Ca2+, the result of which induces neuronal signaling events and propagationglutamate and of actionglycine. potentials. Activation These of this phenomena receptor allowsare requisite influx for the long- term potentiation and depression of pathways that the post- synaptic membrane of neurons, although studies have also notedmediate their higher- presence level inexecutive non-neuronal functions. cells, The including NMDAR astrocytes is present and on oligodendrocytes. At resting potentials, these ligand- gated channels are blocked by Mg2+. Interaction of the NMDAR with glutamate in the synaptic cleft results in depolarization of post- synaptic neurons that 2+ and Na+ +1. However, isthe accompanied synaptic bouton by influx accompanied of Ca by ,a and surfeit efflux of of post-K synaptic Caduring2+ neuropathologies, an excess of glutamate is released from processes that lead to neuronal death2. Thus, NMDARs play a critical role ininflux, not onlyresulting maintaining in a multitude neuronal- of related unfavorable physiology, downstream resulting from synaptic plasticity, but also in pathophysiological diseases, including ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and alcohol dependence3. Page 23 of 32 Holmes AR, Castellino FJ, Balsara RD. The Dichotomous Role of N- methyl- D- Aspartate Receptors in Ischemic Stroke. J Cardiol and Cardiovasc Sciences (2018) 2(4): 23-32 Journal of Cardiology and Cardiovascular Sciences Expression, Structural, and Functional Properties biochemical, pharmacological, and electrophysiological of NMDAR properties to the ion channel in accordance with their 10 (Figure 1). NMDARs can Understanding the various properties of the specificdifferent physiologicaltypes of GluN2 roles subunits, which possess functional physiological and pathological conditions. The NMDAR also exist as triheteromers composed of GluN1 and two NMDAR is integral to defining its functional role under and gating characteristics distinct from the diheteromeric NMDAR11,12 (Figure 2). the functional ion channel is regulated developmentally, temporally,is a heterotetrameric and spatially. complex, The channel and theis composed composition of two of glycine- binding GluN1 subunits and two glutamate- binding GluN2 subunits. The mandatory GluN1 subunit has eight GluN1Expression subunit beginsof the at GluNembryonic subunits day 14is andspatially is present and isoforms (GluN1-1a to 4a and GluN1–1b to 4b) that arise throughouttemporally regulated. the CNS, theAlthough, distribution expression pattern of the of itsubiquitous various from alternative splicing4. There are four different GluN2 isoforms changes depending on the region of the brain, and subunits (GluN2A- D) that are products of independent genes5- 7. Most commonly, the NMDARs found in the forebrain In rodents, the GluN1- 1 isoform is found concentrated in are composed of either two GluN2A or two GluN2B subunits. is based on the alternate splicing of exons 5, 21, and 22. GluN2C-containing NMDARs are ample in the cerebellum, is predominantly found in the thalamus and cerebellum. hippocampus, and amygdala. GluN2D subunits are mainly the cortex and hippocampus, whereas, the GluN1- 4 subunit associated with NMDARs of the hippocampus, brain stem, the dentate gyrus and CA1- 3 layer of the hippocampus. diencephalon, and basal ganglia8. A GluN3 (A/B) subunit The GluN1- 1a isoform lacking exon 5 is found mainly in that binds to glycine and co- assembles with GluN1/GluN2 highly charged amino acids in the N- terminal region is subunits has been more recently discovered9. It is well concentratedThe GluN1- 1b in theisoform CA3 hippocampal containing region.exon The5 encodedGluN1-3 known that the GluN2 subunits impart unique biophysical, 13,14. High levels of GluN2B and subunit is poorly expressed Figure 1: A­schematic­representation­of­the­heterotetrameric­NMDAR­that­consists­of­two­GluN1­subunits­and­two­GluN2(A/B)­subunits.­ The­GluN1­subunit­can­bind­to­glycine,­D-­serine,­7-­Chlorokynurenic­acid­(antagonist),­and­extracellular­protons­(H+),­and­shows­the­ splicing­sites­on­exons­5,­21,­and­22.­The­GluN2(A/B)­subunit­has­the­glutamate­binding­site,­but­can­also­bind­to­various­pharmacological­ agents­in­a­subunit-­dependent­manner.­Ifenprodil­and­conantokin-­G/RlB­are­selective­antagonists­for­the­GluN2B­subunit,­whereas,­ NVP-­AAM077­and­TCN-­201­are­GluN2A-­specific­antagonists.­Extracellular­Zn2+­binds­to­the­GluN2A­subunit­with­high­affinity­(nM)­and­to­ the­GluN2B­subunit­with­low­affinity­(µM).­The­TMD­(1-­4)­topology­that­are­connected­by­linker­regions,­the­amino­terminal­end­(NH2)­ and­the­C-­terminal­domain­(CTD)­are­shown.­Upon­binding­of­the­glutamate/glycine­co-­agonists,­the­Mg2+­block­is­removed­allowing­ influx­of­Ca2+­and­Na+­ions,­and­efflux­of­K+­ions.­The­open­channel­blockers­MK-­801,­ketamine,­and­phencyclidine­are­some­of­the­few­ uncompetitive­NMDAR­antagonists. Page 24 of 32 Holmes AR, Castellino FJ, Balsara RD. The Dichotomous Role of N- methyl- D- Aspartate Receptors in Ischemic Stroke. J Cardiol and Cardiovasc Sciences (2018) 2(4): 23-32 Journal of Cardiology and Cardiovascular Sciences Figure 2: A­schematic­representation­of­various­combinations­of­the­NMDAR­subunits­present­in­the­CNS.­The­functional­NMDAR­ion­ channel­mostly­exists­as­a­diheteromer­consisting­of­GluN1/GluN2A­or­GluN1/GluN2B­subunits.­Triheteromeric­NMDARs­can­be­made­ up­of­GluN1/GluN2A/GluN2B,­GluN1/GluN2C/GluN2D,­or­GluN1/GluN2A/GluN3A/B­subunits.­The­NMDAR­ion­channels­consisting­of­ GluN1/GluN3A/B­subunits­preferentially­bind­to­glycine­over­glutamate. GluN2D are observed in rodent embryos, but within the GluN2B- containing NMDARs suggests this allosteric regulation is due to tight packing of the ATD and LBD. subunit increases. Embryonically, the GluN2B subunit is The TMD of the GluN1a/GluN2B heterotetramer forms a prevalentfirst two weeks in the of brain, birth tobut adulthood after birth levels its distributionof the GluN2A is pseudo-four- fold symmetry due to rearrangement of the M4 helices, an arrangement that aids in regulating the GluN2C subunit is delayed starting at post- natal day 10-11, gating properties22. Additionally, binding of glutamate restricted to regions of the forebrain. Expression of the agonists and competitive antagonists is modulated by GluN2D subunit continues from the embryo to adulthood the LBDs23. The strategically placed helical segments of inand the is mostlydiencephalon, confined mesencephalon,to the cerebellum. and Expression spinal cord of the15. the TMD forms the channel pore that gates the voltage- dependent Mg2+ block, thereby regulating Ca2+ electrophysiological conductance24,25. The cytoplasmic Similarly, the GluN3 subunits have contrasting expression CTD is largely known for partnering with various influx signaling and ofprofiles. the hippocampus, GluN3A expression olfactory is bulb,low in cerebellum the embryonic amygdala, stage thalamus,that peaks and at postnatal hypothalamus, day 8 andin the decreases neocortex, in adulthood CA1 region16. themolecules CTD of and the scaffolding GluN2A, GluN2B,proteins andthat GluN2C form complexes subunits postnatal stages
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