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Glutamate NMDA Receptors in Pathophysiology And ® Postepy Hig Med Dosw (online), 2011; 65: 338-346 www.phmd.pl e-ISSN 1732-2693 Review Received: 2011.02.07 Accepted: 2011.05.11 Glutamate NMDA receptors in pathophysiology and Published: 2011.06.07 pharmacotherapy of selected nervous system diseases Rola receptorów NMDA w patofizjologii i farmakoterapii wybranych chorób układu nerwowego Łukasz Dobrek, Piotr Thor Department of Pathophysiology, Jagiellonian University Medical College Cracow, Poland Summary Glutamate is the basic excitatory neurotransmitter acting via N-methyl-D-aspartate receptors (NMDARs). It co-regulates many important physiological functions, including learning, memo- ry, and behaviour. An excess of glutamate, as well as NMDAR over-activity, produce pathologi- cal effects. Glutamate-related neurotoxicity is involved in the pathogenesis of many neurological conditions. This article briefly describes the role of the glutamate system in the pathophysiology of brain ischemia, selected neurodegenerative disorders, and schizophrenia. It also reviews the current and potential future status of agents targeting NMDARs in neuropsychopharmacology. Key words: glutamate • NMDA receptors (NMDARs) • excitotoxicity • NMDAR antagonists Streszczenie Glutaminian jest podstawowym neuroprzekaźnikiem pobudzającym, który działa na receptory NMDA. Związek ten jest współodpowiedzialny za regulowanie wielu ważnych fizjologicznych funkcji, wliczając w to uczenie się, pamięć i zachowanie. Nadmiar glutaminianu i nadaktywność receptorów NMDARs wywołuje patologiczne zmiany. Zjawisko neurotoksyczności zależnej od glutaminianu bierze udział w patogenezie wielu zaburzeń neurologicznych. Artykuł pokrótce opisuje rolę glutaminianu w patofizjologii udaru niedokrwiennego mózgu, wybranych chorób neurodegeneracyjnych i schizofrenii oraz omawia obecne i potencjalne znaczenie leków działa- jących na receptory glutaminergiczne w neuropsychofarmakologii. Słowa kluczowe: glutaminian • receptory NMDA • neurotoksyczność glutaminianu • antagoniści receptora NMDA Full-text PDF: http://www.phmd.pl/fulltxt.php?ICID=946637 Word count: 4925 Tables: 1 Figures: 1 References: 28 Author’s address: Łukasz Dobrek, M.D., Department of Pathophysiology, Jagiellonian University Medical College, Czysta Street 18, 31-121 Cracow, Poland; e-mail: [email protected] 338 ® Postepy Hig Med Dosw (online), 2011; 65 338 Dobrek Ł. and Thor P. – Glutamate NMDA receptors in pathophysiology… Abbreviations: AD – Alzheimer’s disease; ALS – Amyotrophic lateral sclerosis; AMPAR – a-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptor; CJD – Creutzfeld-Jacob disease; EAATs – Excitatory aminoacids transporters; GABA – g-aminobutyric acid; glyT1 – glycine transporter 1; HD – Huntington disease; KAR – Kainate receptor; LTD – Long term depression; LTP – Long term potentiation; MAPK – Mitogen activated protein kinase; NMDAR – N-methyl-D-aspartate receptor; PD – Parkinson disease; PSD – Postsynaptic density; TBI – Traumatic brain injury. 1. GLUTAMATE RECEPTORS Considering the NMDAR molecular structure, one may surmise that they have a common membrane topology In mammalian central nervous system synapses, glutama- with a large extracellular N-terminus, a membrane region te is the major neurotransmitter mediating excitatory neu- composed of three transmembrane segments, and differ rotransmission. It is released from presynaptic vesicles, in the cytoplasmic C-terminus, depending on the vario- diffuses across the synaptic cleft, and acts on both me- us subunits, which interacts with numerous intracellular tabotropic and ionotropic glutamate receptors located in proteins [3,22]. the presynaptic terminals and postsynaptic membranes of the brain and spinal neurons. Three ionotropic glutamate Opening of the channel pore by NMDAR requires the si- receptor subtypes can be distinguished, and they are na- multaneous binding of the major agonist – glutamate (which med according to their agonists: NMDAR (N-methyl-D- play a neurotransmitter role) and the co-agonist – glyci- aspartate receptor), AMPAR (a-amino-3-hydroxy-5-me- ne (or D-serine, which act as modulators). The glutama- thylisoxazole-4-propionic acid receptor) and KAR (kainate te binding site is located on the NR2 subunit, whereas the receptor). NMDARs are composed of protein complexes glycine binding site is located on the NR1 subunit. After which form an intrinsic ion channel, permeable to mono- presynaptic glutamate release, and with sufficient glycine valent cations (including Na+ and K+), and bivalent ones concentration in the synaptic cleft, NMDAR activation takes (mostly Ca2+). We also know of a metabotropic glutamate place. When the membrane is depolarised, the voltage-de- receptor coupled to a G intrinsic membrane protein [12,13]. pendent Mg2+ block is removed from the channel interior, allowing for ion to enter. By contrast, AMPARs, composed NMDARs contain four subunits which are a combination of: of various combinations of four subunits ( GluR1-GluR4) NR1, NR2, and NR3, (encoded by genes GRIN1, GRIN2A-D, are permeable to Ca2+ only in the absence of the GluR2 GRIN3A-B, respectively). There is consensus that NMDARs element [3,12,13,22]. are tetramers composed of two NR1 subunits and two NR2 subunits, less commonly including NR3 subunits. NR1 sub- The general scheme of NMDA receptor structure together units exhibit basic NMDAR features and disruption of NR1 with the potential sites for pharmacological action descri- genes abolishes NMDAR responses. This demonstrates that bed below presents figure 1. NR1 subunits are rather essential. There are eight different NR1 elements, generated by alternative splicing of a single NMDARs can be divided into two classes according to the- gene. Four (A-D) NR2 compounds can be distinguished, ir conductance properties: high conductance channels (bu- located in various brain regions and playing a modulatory ilt from NR2A or NR2B) and low conductance ones (for- role in regards to NMDARs. It has been shown that the com- med by NR2C and NR2D) with reduced sensitivity to Mg2+ bination of NR1 with different NR2 subunits results in di- block. An influx of extracellular calcium initiates complex verse electrophysiological and pharmacological responses. signalling pathways compromised of the mitogen-activa- NR1 and NR2A are ubiquitous, NR2B occurs in the fore- ted protein kinase (MAPK) superfamily that transduces brain, NR2C in the cerebellum, with NR2D being the rarest. excitatory signals across the neuron. Taking into conside- There is a binding place in the channel pore for Mg2+, and ration in vitro substances, MAPKs have been also called at resting membrane potential, Mg2+ is attached to this bin- microtubule associated protein-2 kinase (MAP-2 kinase), ding site, blocking ion flow through the channel [3,12,22]. myelin basic protein kinase (MBP kinase), ribosomal S6 protein kinase (RSK-kinase) and epidermal growth factor Generally, NMDARs occur in many but not all cerebral (EGF) receptor threonine kinase (ERT kinase). MAPK ac- cortex neurons and some cortical astrocytes. They are mo- tivation was observed in response to NMDARs stimulation, stly located on dendrites. Immunocytochemical studies starting with tyrosine phosphorylation of MAPKs. An ad- have revealed that NMDARs are less frequently found in ditional class of kinases, named MAP kinase kinases and the 4th layer than in layers 2 to 3 and 5 to 6, where they are MAPK kinase kinases (MAPKK kinases), are then excited, preferentially expressed by pyramidal neurons. This is in through an intermediate step involving MAPK stimulation. agreement with the notion that afferent glutaminergic in- Usually, three MAPKs are distinguished: extracellular si- put reaches the cerebral cortex through the thalamocortical gnal-regulated kinase-1 (ERK1 and 2), the Jun N-terminal pathway, formed by axons of the 4th layer. NMDA recep- kinases (JNKs) activating Jun transcription factor, and the tors are localised in the postsynaptic membrane, organised p38 MAPKs. The two last ones are called stress-activated by a multi-protein structure called the postsynaptic densi- kinases (SAPKs), because they are stimulated by stressful ty (PSD). These receptors, however, are mobile and move conditions. Consequently, the transcription factor cAMP- between the synaptic and extra-synaptic pools. The PSD -Ca2+ response element-binding protein (CREB) causes is defined as a type of postsynaptic membrane that conta- the expression of genes that encode brain-derived neuro- ins high concentrations of glutamate receptors, ion chan- trophic factor (BDNF) and other factors promoting neuro- nels, kinases, phosphatases and associated proteins [2,13]. nal survival and activity [5,9,24,27]. Detailed information 339 Postepy Hig Med Dosw (online), 2011; tom 65: 338-346 Fig. 1. NMDA receptor scheme and selected NMDAR- based pharmacological strategies for treatment voltage gated [12,22] channels inhibitors presynaptic neuron neurotransmitter glia Glycine NR1 site glutamate reuptake Glutamate NR2 site enhancers EAAT NR NR 1 2 tetrameric NMDA receptor NMDAR antagonists signalling pathway NR1 subunit-kinase, signalling protein phospatase modulators NR2 subunit-scaold protein, signalling enzyme MAPK gene transcription postsynaptic neuron concerning NMDAR and MAPK signalling is given in an 2. GLUTAMATE AND SYNAPTIC PLASTICITY excellent review prepared by Haddad [9]. The glutamate system is thought to be involved in learning AMPARs, similar to NMDARs, couple to the MAPK pa- and memory processes. It is associated with the phenomenon thways through similar sets
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