Structure, function, and pharmacology of nmda receptor. Although most glutamate receptors are cation selective,fewarepermeabletocalciumions. The authors used in situ hybridization to determine nmdar1, nmdar2anmdar2d, glur1glur7, ka1, and ka2 subunit mrna levels and receptor autoradiography to determine binding to glutamate binding sites of the three receptor subtypes and to the glycine, polyamine, and ion channel binding sites of the nmda receptor. Nmda receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein reelin.
In vivo iglurs occur predominantly as heteromers of different subunit types and isoforms. Altered transcript expression of nmda receptorassociated. Modulation of nmda receptor properties and synaptic. Sensitivity to glutamate and channel kinetics depend on the subunit composition pubmed. Accumulating evidences suggest that the primary excitatory i. The nmda receptor is an important protein in the brain which is involved in physiological processes such as synaptic transmission and synaptic plasticity which may underlie learning and memory. They are commonly used as anesthetics for animals and humans. The subunit composition of nmda receptors nmdars determines their biophysical, pharmacological and signalling properties. Subunit arrangement and function in nmda receptors article pdf available in nature 4387065. Activation mechanisms of the nmda receptor biology of. The nmda receptor is a glutamate and ion channel protein receptor that is activated when glycine and glutamate bind to it. Paolettirelating nmda receptor function to receptor subunit composition. Mechanisms underlying nmda receptor synapticextrasynaptic distribution and function.
Nmda receptors are proteins that are embedded in the membrane of postsynaptic neurons. Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Therefore, it is not surprising that this receptor has been widely studied. Jun 19, 2006 we initially found reduced nmda receptor subunit transcripts nr1 and nr2c, and decreased polyamine and glycine binding sites of the nmda receptor complex in limbic thalamic nuclei in schizophrenia, but we did not find prominent changes in the expression of ampa, kainate or metabotropic receptors ibrahim et al. Nmda receptor subunits and mental disorders current molecular medicine, 2015, vol. The nmda glutamate receptor consists of several subunits, including the. Current molecular medicine 2015, specific roles of nmda. Both nr1 and nr2 consist of n atd and c ctd terminal domains, a transmembrane domain tm and a s1s2 ligandbinding core. Jan 01, 2006 relating nmda receptor function to receptor subunit composition. May 20, 20 the subunit composition of nmda receptors nmdars determines their biophysical, pharmacological and signalling properties. The other receptors are the ampa and kainate receptors. This finding also offers additional reasons to explain why. Nmda receptor structures reveal subunit arrangement and.
Nmda receptor antagonists induce a state called dissociative anesthesia, marked by catalepsy, amnesia, and analgesia. In particular, nmdars contain a diversity of sites at which endogenous ligands or pharmacological agents can act to modulate receptor activity in a subunitselective manner, and. Altered nr 1 subunit isoforms may reflect changes in nmda receptor subunit composition, which in turn may have significant functional consequences, since alternative splicing of exons 5, 21, and 22 can modulate nmda receptor localization and function 33, 34, 46. Glutamic acid glu is the major excitatory neurotransmitter in the central nervous system, and interacts with two classes of receptor. Nmda receptor channel blockers act by binding to the pore of the nmda receptor channel and are therefore noncompetitive antagonists. Grin2b glutamate receptor ionotropic, nmda 2b precursor. Nmda receptors and signaling in chronic neuropathic pain. The regulatory subunit composition of nmdars defines its pharmacological and kinetic properties 35, 9, 12.
It gets its name from a drug that specifically activates it. The nmda subtype of glutamate receptor is known to exhibit marked changes in subunit composition and functional properties during neural development. Pharmacology of nmda receptors biology of the nmda receptor. Changing subunit composition of heteromeric nmda receptors. Expression of regulatory subunits is dynamic and seems to be tightly regulated in time and space 4, 12. Nmethyldaspartate nmda receptors are hebbianlike coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltagedependent magnesium block to open. Mk801 is a commonly used, high affinity non competitive antagonist. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane. The subunit composition of a nmethyldaspartate nmda receptor, which dictates most aspects of its function, can vary between neurons in. Polyamines modulate nmda receptor function and bind to a site on the glun2b subunit.
Pdf subunit arrangement and function in nmda receptors. During forebrain development, there is a shift in nmdar subunit composition, from nearexclusively glun2bcontaining nmdars to nmdars. Active camkii can bind to nmdars, but the physiological role of this interaction is not well understood. The nmethyldaspartate receptor also known as the nmda receptor or nmdar, is a glutamate receptor and ion channel protein found in nerve cells. Conventional nmdar consist of heterotetrameric structures composed of glun1 and glun2 subunits. Importantly, synapse formation and subsequent maturation within single neurons are processes that occur throughout the lifetime of an animal and contribute to synaptic plasticity during. Nmdar schematic diagram, crystal structures and subtypedependent properties a, schematic diagram of an assembled diheteromeric nmdar upper with an enlarged schematic diagram of a single nmdar subunit depicting the distinct functional domains lower. Therapeutic targeting of the pathological triad of. To determine the role of individual nr2 subunits in nmdar signaling, i examined the biochemical interactions and colocalization.
The diversity in subunit composition creates nmda receptor subtypes with distinct physiological roles across neuronal cell types and brain regions, and enables precise tuning of synaptic transmission. Ethanol is a small molecule acting on several neurotransmitter systems in the brain. Ionotropic receptors are divided according to the affinity of their specific agonists. The results underline the pivotal role of glutamate in frontal lobe function and indicate that the nr3a subunit could be a plausible candidate gene. Glutamate the conjugate base of glutamic acid is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the bodys most prominent neurotransmitter, the brains main excitatory. Characterization of a soluble ligand binding domain of the nmda receptor regulatory subunit nr3a. Jan 01, 20 mcilhinney, nmethyldaspartate nmda receptor subunit nr1 forms the substrate for oligomeric assembly of the nmda receptor, journal of biological chemistry, vol. Longterm potentiation ltp is a form of synaptic plasticity proposed as a cellular mechanism of memory formation. Enhanced nr2a subunit expression and decreased nmda receptor. We initially found reduced nmda receptor subunit transcripts nr1 and nr2c, and decreased polyamine and glycine binding sites of the nmda receptor complex in limbic thalamic nuclei in schizophrenia, but we did not find prominent changes in the expression of ampa, kainate or metabotropic receptors ibrahim et al. It was shown for the first time that the genetic constitution of the subunit composition of nmda receptor regulation might be relevant for prefrontal information processing in humans. The glun2b subunit also posesses a binding site for ployamines, regulatory molecules that modulate the functioning of the nmda receptor.
Our results indicate that targeting synaptic nmda receptor subunit composition may represent an intriguing therapeutic approach aimed at. Specific assembly with the nmda receptor 3b subunit controls surface expression and calcium permeability of nmda receptors. Nmda receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the nmethyldaspartate receptor. Subunit composition is an important determinant for nmdar deactivation kinetics and intracellular calcium dynamics, as discussed in chapter 9. The nmda receptor functions as a modulator of synaptic response and a coincidence detector. Nmda short for nmethyldaspartate receptor antagonists are a class of drugs that may help treat alzheimers disease, which causes memory loss, brain damage, and, eventually, death. Nov 10, 2005 a, domain organization of nmda receptor subunits. A third subunit, glun3, can also assemble with nmdar subunits giving a remarkable modification of their heteromeric structure, forming a. Most studies have focused on the functional significance of the exon 5encoded n1. Gray ja, shi y, usui h, during mj, sakimura k, nicoll ra. In particular, nmdars contain a diversity of sites at which endogenous ligands or pharmacological agents can act to modulate receptor activity in a subunitselective.
Glun2 subunits contain the glutamatebinding site anson et al. Nmda receptors nmdars are ionotropic glutamate receptors, which play a critical role in excitatory neurotransmission in the central nervous system cns. Ionotropic glutamate receptor binding and subunit mrna. Nmdatype glutamate receptors nmdar regulate neurotransmission and excitotoxicity. The prevailing idea is that nmda receptormediated synaptic responses decrease in duration after the peak of cortical plasticity in rodents. The timing of subunit changes between e17 and e18 is coincident with the prenatal emergence of rhythmical jaw movements, and in vitro rhythmical trigeminal activity, shown in earlier studies. Receptor localization and subunit composition at excitatory synapses, nmda receptors are embedded in thepostsynapticmembrane,wheretheyareorganizedbya multiprotein structure called the postsynaptic density psd. Here, we test if association between active camkii and synaptic nmdars is required for synaptic plasticity. Enhanced nr2a subunit expression and decreased nmda. Our data suggest that nmda receptor plays an important role in the development and function of prenatal oralmotor circuits. The diversity in subunit composition creates nmda receptor subtypes with distinct physiological roles across neuronal cell types and brain regions, and. Glutamate the conjugate base of glutamic acid is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the bodys most prominent neurotransmitter, the brains main excitatory neurotransmitter, and also.
At resting membrane potentials, nmda receptors are inactive. An nmda receptor subunit with exquisite properties. On the synaptic level, changes in nmdar subunit composition and nmdarmediated synaptic activity clearly contribute to the maturation of glutamatergic synapses. The antigen is a peptide from the nterminus of the nr2b subunit of rat nmda receptor. Relating nmda receptor function to receptor subunit composition. Nmethyldaspartate receptors nmdar are pivotal for synaptic plasticity and memory formation.
Nmda receptor activation leads to opening of an ion channel that is selective for cations, resulting in the influx of na. Limitations of the pharmacological approach jacques neyton, pierre paoletti journal of neuroscience 1 january 2006, 26 5 3133. Nmdars exist as multiple subtypes that differ in their molecular subunit composition. In the ca1 region of the hippocampus, a region in which this form of plasticity has been most extensively examined, a number of required molecular processes have been identified, including the opening of nmdatype glutamate receptors nmdars and. Biology of the nmda receptor frontiers in neuroscience. Nmda receptors nmdars are ion channels gated by the excitatory neurotransmitter glutamate. Nmdars occur as multiple subtypes which differ in their subunit composition and in their biophysical and pharmacological properties. To investigate the mechanisms underlying neurotransmitter receptor clustering, we expressed the nmda nmethyldaspartate receptor nr1a subunit in human embryonic kidney hek 293 cells. The receptor is a heteromeric complex that interacts with multiple intracellular proteins by three different subunits.
Nmda receptor, nr1 subunit, nr2 subunit, isoform, excitotoxicity. Prototypic agonist at the nmdatype glutamate receptor that regulates ion channels. Several subunits of the nmda receptor have been cloned. Nmda receptors and brain development biology of the nmda.
Controlling nmda receptor subunit composition using. Nmda receptor subunit composition controls synaptic plasticity by regulating binding to camkii. Grin2a glutamate receptor ionotropic, nmda 2a precursor. In concert with dapk1 at extrasynaptic sites, acts as a central mediator for stroke damage. Jul 22, 2006 neyton j, paoletti p 2006 relating nmda receptor function to receptor subunit composition.
Distinct modes of ampa receptor suppression at developing synapses by glun2a and glun2b. Structure, function, and pharmacology of nmda receptor channels. Plasticity of nmda receptor nr2b subunit in memory and. However, despite the importance of rhythms for the sustenance of life, this aspect of nmdar function remains poorly studied. Nmda receptor nr2b subunit nterminus antibody phosphosolutions. Component of nmda receptor complexes that function as heterotetrameric, ligandgated ion channels with high calcium permeability and voltagedependent sensitivity to magnesium pubmed. Nmda type glutamate receptors nmdar regulate neurotransmission and excitotoxicity.
The developmental shift of nmda receptor composition proceeds. The nmethyldaspartate nmda receptors are made up of five subunits that have a similar amino acid sequence to other glutamate membrane receptor classes such as the ampa. Pathological changes involving the nmda receptors probably contribute to the development of epilepsy, acute neuronal damage such as that resulting from. It is found in the hippocampal formation, especially in field ca1. Despite being anchored to the psd, nmda receptors are mobile and move laterally between synaptic and extrasynaptic pools 7. The nmda receptor plays a critical role in the development of the central nervous system and in adult neuroplasticity, learning, and memory. The amount of ca influx resulting from nmdar activation is further modulated by other external physiological factors including ph, zinc ions, and polyamines that are discussed in chapters 11 and 12. Notwithstanding limitations of using pharmacology alone in relating nmdar function and receptor subunit composition neyton and paoletti 2006, the compounds chosen were those that enabled us to distinguish between di and triheteromeric nmdars at intracortical synapses initially kumar and huguenard 2003. Nmda receptors centre for synaptic plasticity university.
Temporal and regional expression of nmda receptor subunit nr3a in the mammalian brain. Itsexceptional calcium permeability is the first of two key properties of the nmda receptor that. Nmda receptor function and physiological modulation. Influence of glun2 subunit identity on nmda receptor function. Mcilhinney, nmethyldaspartate nmda receptor subunit nr1 forms the substrate for oligomeric assembly of the nmda receptor, journal of biological chemistry, vol. Subunit arrangement and function in nmda receptors nature. Nmethyldaspartic acid nmda plays a crucial role in release of luteinizing hormone and prl prolactin in the pituitary gland and gnrh gonadotropin releasing hormone in the hypothalamus.
Relating nmda receptor function to receptor subunit. Colocalization of distinct nmda receptor subtypes at excitatory. Nmda receptor subunit composition controls synaptic. Calcium entry through postsynaptic nmdars and subsequent activation of camkii trigger synaptic plasticity in many brain regions. In nmda receptor nr2b subunit genetically overexpression mice, we found that chronic pain but not acute or physiological pain was selectively enhanced 30, 42 see figure 2, providing the first genetic evidence that forebrain nmda nr2b receptor is critical for chronic pain.
In the ca1 region of the hippocampus, a region in which this form of plasticity has been most extensively examined, a number of required molecular processes have been identified, including the opening of nmda type glutamate receptors nmda rs and the consequent. Glutamate receptor ion channels iglurs mediate excitatory transmission and synaptic plasticity in the brain traynelis et al. The precise subunit composition of these oligodendroglial nmdars is unknown. The nmda receptor is one of three types of ionotropic glutamate receptors. Nmda receptor glun2aglun2b subunit ratio as synaptic. The antibody is prepared from rabbit serum by affinity purification using a column to which the peptide immunogen was coupled. Nmdars are cationic channels permeable to sodium, potassium and calcium. Ketamine is a favored anesthetic for emergency patients with unknown medical history and in the treatment of burn victims because it depresses breathing and circulation less than other anesthetics.
Nmda receptor subunits change after synaptic plasticity. The subunit composition of the receptors within and outside synaptic contacts is similar, although, in addition to carrying the common glun1 subunit, extrasynaptic nmda receptors contain preferentially the glun2b subunit, whereas glun2a is the predominant subunit in synaptic nmda receptors paoletti et al. The diversity of nmdar subunits and their unique developmental and spatial. Genetic variations of the nr3a subunit of the nmda receptor. Structure, function, and allosteric modulation of nmda receptors. Nmdar signaling is believed to be dependent on nr2 subunit ad composition and interactions with intracellular proteins.
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