Glutamate is the main excitatory synaptic transmitter between neurones in the central nervous system. The excitatory effect of glutamate is due to activation of two distinct types of receptor ion channels-AMPA/kainate and NMDA type. This article reviews recent discoveries concerning molecular structure of NMDA receptor channels, its pharmacology and biophysics including excitatory postsynaptic currents mediated by activation of this subtype of glutamate receptor.

• MeSH
• lidé MeSH
• receptory N-methyl-D-aspartátu * účinky léků   metabolismus   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• receptory N-methyl-D-aspartátu * MeSH

Astrocytes support glutamatergic neurotransmission in the central nervous system through multiple mechanisms which include: (i) glutamate clearance and control over glutamate spillover due to operation of glutamate transporters; (ii) supply of obligatory glutamate precursor glutamine via operation of glutamate-glutamine shuttle; (iii) supply of L-serine, the indispensable precursor of positive NMDA receptors neuromodulator D-serine and (iv) through overall homoeostatic control of the synaptic cleft. Astroglial cells express an extended complement of ionotropic and metabotropic glutamate receptors, which mediate glutamatergic input to astrocytes. In particular a sub-population of astrocytes in the cortex and in the spinal cord express specific type of NMDA receptors assembled from two GluN1, one GluN2C or D and one GluN3 subunits. This composition underlies low Mg2+ sensitivity thus making astroglial NMDA receptors operational at resting membrane potential. These NMDA receptors generate ionic signals in astrocytes and are linked to several astroglial homoeostatic molecular cascades.

• Klíčová slova
• Astrocyte, Glutamate, NMDA receptors, Neurotransmitters,
• MeSH
• astrocyty metabolismus   MeSH
• lidé MeSH
• membránové potenciály fyziologie   MeSH
• mozková kůra metabolismus   MeSH
• nervová síť metabolismus   MeSH
• receptory N-methyl-D-aspartátu metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• receptory N-methyl-D-aspartátu MeSH

Excessive stimulation of NMDA receptors with glutamate or other potent agonists such as NMDA leads to excitotoxicity and neural injury. In this study, we aimed to provide insight into an animal model of brain excitotoxic damage; single unilateral infusion of NMDA at mild dose into the hippocampal formation. NMDA infusion induced chronic, focal neurodegeneration in the proximity of the injection site. The lesion was accompanied by severe and progressive neuroinflammation and affected preferentially principal neurons while sparing GABAergic interneurons. Furthermore, the unilateral lesion did not cause significant impairment of spatial learning abilities. Finally, GluN1 and GluN2B subunits of NMDA receptor were significantly upregulated up to 3 days after the NMDA infusion, while GABAA α5 subunit was downregulated at 30 days after the lesion. Taken together, a single infusion of NMDA into the hippocampal formation represents an animal model of excitotoxicity-induced chronic neurodegeneration of principal neurons accompanied by severe neuroinflammation and subunit specific changes in NMDA and GABAA receptors.

• Klíčová slova
• Carousel maze, Excitotoxicity, GABA A receptor, Hippocampus, Interneurons, NMDA receptor, Neurodegeneration, Neuroinflammation, Spatial learning,
• MeSH
• bludiště - učení účinky léků   fyziologie   MeSH
• degenerace nervu diagnostické zobrazování   metabolismus   patologie   MeSH
• funkční lateralita MeSH
• hipokampus diagnostické zobrazování   účinky léků   metabolismus   patologie   MeSH
• modely nemocí na zvířatech MeSH
• N-methylaspartát aplikace a dávkování   toxicita   MeSH
• neurodegenerativní nemoci diagnostické zobrazování   metabolismus   patologie   MeSH
• neuroimunomodulace fyziologie   MeSH
• neurony účinky léků   metabolismus   patologie   MeSH
• potkani Long-Evans MeSH
• receptory GABA-A metabolismus   MeSH
• receptory N-methyl-D-aspartátu metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Gabra5 protein, rat MeSH Prohlížeč
• N-methylaspartát MeSH
• NR1 NMDA receptor MeSH Prohlížeč
• NR2B NMDA receptor MeSH Prohlížeč
• receptory GABA-A MeSH
• receptory N-methyl-D-aspartátu MeSH

Repeated administration of psychostimulants and other dependence-producing substances induces a substantial increase in behavioural responses, a phenomenon termed as behavioural sensitization. An increased response to the tested drug elicited by previous repeated administration of a different drug is called cross-sensitization. Behavioural sensitization is considered to be a relapse trigger in dependent subjects and animals sensitized by repeated administration of drugs of abuse, thus being considered a suitable model of craving, which is one of the very characteristic features of substance addiction. It has been described that apart from other actions, drugs of abuse exert their effect on the central nervous system by affecting glutamatergic transmissions, particularly via N-methyl-d-aspartate (NMDA) receptors. Thus, this review presents a brief overview of the impact of inhibition of the NMDA receptor system on sensitization, reflecting particularly on behavioural sensitization to psychostimulants. The text combines up-to-date information with time-proven facts and also compares data from the literature with the authors׳ recent findings concerning this topic.

• Klíčová slova
• Animal models, Behavioural sensitization, NMDA receptor, Psychostimulants,
• MeSH
• chování zvířat účinky léků   MeSH
• lidé MeSH
• receptory N-methyl-D-aspartátu metabolismus   MeSH
• stimulanty centrálního nervového systému farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• receptory N-methyl-D-aspartátu MeSH
• stimulanty centrálního nervového systému MeSH

• MeSH
• buněčná membrána fyziologie   ultrastruktura   MeSH
• lidé MeSH
• receptory N-methyl-D-aspartátu fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• receptory N-methyl-D-aspartátu MeSH

Ionotropic glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype are highly expressed in the central nervous system and are involved in excitatory synaptic transmission and synaptic plasticity. Prolonged activation of NMDA receptors can lead to excitotoxicity, which is implicated in the pathogenesis of neurodegeneration occurring in various acute and chronic disorders of the central nervous system. Recent advances in understanding the function, pharmacology, genetics and structure of NMDA receptors has promoted a search for new compounds that could be therapeutically used. These compounds act on agonist binding sites, either apart from them or directly within the ion channel pore. Members of the last group are called open channel blockers, and some of them, such as memantine and ketamine, are already clinically used. Kinetic modeling of NMDA receptor activity was employed to define the effects of various groups of modulators. Quantifying the action of these substances by kinetic parameters can help us to reveal the molecular mechanism of action at the receptor and to characterize the dependence of its action on the mode of NMDA receptor activation. Two modes are considered: phasic activation, induced by synaptically released glutamate, and tonic activation, which is expected to occur under pathological conditions when low, but sustained levels of glutamate activate NMDA receptors. The aim of our review is to summarize the recent data about the structural and functional properties of NMDA receptors and their role in long-term potentiation and excitotoxicity.

• MeSH
• degenerace nervu patofyziologie   MeSH
• glycin metabolismus   MeSH
• iontové kanály metabolismus   MeSH
• kyselina glutamová metabolismus   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• oxidace-redukce MeSH
• receptory N-methyl-D-aspartátu agonisté   chemie   účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• glycin MeSH
• iontové kanály MeSH
• kyselina glutamová MeSH
• receptory N-methyl-D-aspartátu MeSH

Pregnenolone sulfate (PS), an endogenously occurring neurosteroid, has been shown to modulate the activity of several neurotransmitter-gated channels, including the NMDA receptor (NMDAR). NMDARs are glutamate-gated ion channels involved in excitatory synaptic transmission, synaptic plasticity, and excitotoxicity. In this study, we analyzed the effects of PS on calcium signaling in cultured hippocampal neurons and HEK293 cells expressing NMDAR. The cells were loaded with the Ca(2+) sensor Fura-2. In agreement with previous electrophysiological experiments, PS potentiated the increases in intracellular Ca(2+) induced by an exogenous application of glutamate; however, PS also increased intracellular Ca(2+) in the absence of exogenous NMDA agonist. The agonist-independent effect of PS was induced in all neurons studied and in HEK293 cells expressing GluN1/GluN2A-B receptors in a neurosteroid-specific manner. We conclude that PS is an endogenous NMDA agonist that activates the GluN1/GluN2A-B receptors.

• MeSH
• gating iontového kanálu fyziologie   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• pregnenolon metabolismus   MeSH
• receptory N-methyl-D-aspartátu metabolismus   MeSH
• vápník metabolismus   MeSH
• vápníková signalizace fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• pregnenolon MeSH
• pregnenolone sulfate MeSH Prohlížeč
• receptory N-methyl-D-aspartátu MeSH
• vápník MeSH

We report the first complete description of the molecular mechanisms behind the transition of the N-methyl-d-aspartate (NMDA) receptor from the state where the transmembrane domain (TMD) and the ion channel are in the open configuration to the relaxed unliganded state where the channel is closed. Using an aggregate of nearly 1 µs of unbiased all-atom implicit membrane and solvent molecular dynamics (MD) simulations we identified distinct structural states of the NMDA receptor and revealed functionally important residues (GluN1/Glu522, GluN1/Arg695, and GluN2B/Asp786). The role of the "clamshell" motion of the ligand binding domain (LBD) lobes in the structural transition is supplemented by the observed structural similarity at the level of protein domains during the structural transition, combined with the overall large rearrangement necessary for the opening and closing of the receptor. The activated and open states of the receptor are structurally similar to the liganded crystal structure, while in the unliganded receptor the extracellular domains perform rearrangements leading to a clockwise rotation of up to 45 degrees around the longitudinal axis of the receptor, which closes the ion channel. The ligand-induced rotation of extracellular domains transferred by LBD-TMD linkers to the membrane-anchored ion channel is responsible for the opening and closing of the transmembrane ion channel, revealing the properties of NMDA receptor as a finely tuned molecular machine.

• Klíčová slova
• NMDA receptor transition, glutamate receptor gating, molecular dynamics simulations, molecular modeling, open and closed state,
• MeSH
• krysa rodu Rattus MeSH
• receptory N-methyl-D-aspartátu chemie   metabolismus   MeSH
• simulace molekulární dynamiky * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• receptory N-methyl-D-aspartátu MeSH

We aimed to prepare novel dibenzo [a,d][7]annulen derivatives that act on N-methyl-d-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Our in silico analyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds 3l and 6f to penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy, 6f showed high relative inhibition (∼90 % for GluN1/GluN2A), while 3l showed moderate inhibition (∼50 %). An in vivo toxicity study determined that compounds 3l and 6f were safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compound 3l at a concentration of 30 μM significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzo [a,d][7]annulen derivatives are promising candidates for developing NMDA receptor-targeted therapies with minimal psychotomimetic side effects.

• Klíčová slova
• Acetylcholinesterase, Alzheimer's disease, Electrophysiology, Ionotropic glutamate receptor, NMDA receptor, Neuroprotection,
• MeSH
• dizocilpinmaleát * farmakologie   MeSH
• hematoencefalická bariéra metabolismus   účinky léků   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• molekulární struktura MeSH
• neuroprotektivní látky * farmakologie   chemie   chemická syntéza   MeSH
• potkani Sprague-Dawley MeSH
• receptory N-methyl-D-aspartátu * antagonisté a inhibitory   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dizocilpinmaleát * MeSH
• neuroprotektivní látky * MeSH
• receptory N-methyl-D-aspartátu * MeSH

NMDA receptors have received much attention over the last few decades, due to their role in many types of neural plasticity on the one hand, and their involvement in excitotoxicity on the other hand. There is great interest in developing clinically relevant NMDA receptor antagonists that would block excitotoxic NMDA receptor activation, without interfering with NMDA receptor function needed for normal synaptic transmission and plasticity. This review summarizes current understanding of the structure of NMDA receptors and the mechanisms of NMDA receptor activation and modulation, with special attention given to data describing the properties of various types of NMDA receptor inhibition. Our recent analyses point to certain neurosteroids as NMDA receptor inhibitors with desirable properties. Specifically, these compounds show use-dependent but voltage-independent block, that is predicted to preferentially target excessive tonic NMDA receptor activation. Importantly, neurosteroids are also characterized by use-independent unblock, compatible with minimal disruption of normal synaptic transmission. Thus, neurosteroids are a promising class of NMDA receptor modulators that may lead to the development of neuroprotective drugs with optimal therapeutic profiles.

• MeSH
• gating iontového kanálu účinky léků   MeSH
• konformace proteinů MeSH
• lidé MeSH
• mozek účinky léků   metabolismus   MeSH
• nemoci mozku farmakoterapie   metabolismus   MeSH
• nervový přenos účinky léků   MeSH
• neurony účinky léků   metabolismus   MeSH
• neuroprotektivní látky terapeutické užití   MeSH
• receptory N-methyl-D-aspartátu chemie   účinky léků   metabolismus   ultrastruktura   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• neuroprotektivní látky MeSH
• receptory N-methyl-D-aspartátu MeSH