WordNet

a cellular structure that is postulated to exist in order to mediate between a chemical agent that acts on nervous tissue and the physiological response

PrepTutorEJDIC

=sense organ / 受信装置

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/08/18 23:33:52」(JST)

wiki en

[Wiki en表示]

NMDA

Glutamic acid

Stylised depiction of an activated NMDAR. Glutamate is in the glutamate-binding site and glycine is in the glycine-binding site. Allosteric sites that would cause inhibition of the receptor are not occupied. NMDARs require the binding of two molecules of glutamate or aspartate and two of glycine.^[1]

The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function.^[2]

The NMDAR is a specific type of ionotropic glutamate receptor. NMDA (N-methyl-D-aspartate) is the name of a selective agonist that binds to NMDA receptors but not to other glutamate receptors. Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations with an equilibrium potential near 0 mV. A property of the NMDA receptor is its voltage-dependent activation, a result of ion channel block by extracellular Mg²⁺ & Zn²⁺ ions. This allows the flow of Na⁺ and small amounts of Ca²⁺ ions into the cell and K⁺ out of the cell to be voltage-dependent.^[3]^[4]^[5]^[6]

Calcium flux through NMDARs is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory. The NMDA receptor is distinct in two ways: first, it is both ligand-gated and voltage-dependent; second, it requires co-activation by two ligands: glutamate and either D-serine or glycine.^[7]

Structure

The NMDA receptor forms a heterotetramer between two GluN1 and two GluN2 subunits (the subunits were previously denoted as NR1 and NR2), two obligatory NR1 subunits and two regionally localized NR2 subunits. A related gene family of NR3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor isoforms with distinct brain distributions and functional properties arise by selective splicing of the NR1 transcripts and differential expression of the NR2 subunits.

Each receptor subunit has modular design and each structural module also represents a functional unit:

The extracellular domain contains two globular structures: a modulatory domain and a ligand-binding domain. NR1 subunits bind the co-agonist glycine and NR2 subunits bind the neurotransmitter glutamate.

The agonist-binding module links to a membrane domain, which consists of three trans-membrane segments and a re-entrant loop reminiscent of the selectivity filter of potassium channels.

The membrane domain contributes residues to the channel pore and is responsible for the receptor's high-unitary conductance, high-calcium permeability, and voltage-dependent magnesium block.

Each subunit has an extensive cytoplasmic domain, which contain residues that can be directly modified by a series of protein kinases and protein phosphatases, as well as residues that interact with a large number of structural, adaptor, and scaffolding proteins.

The glycine-binding modules of the NR1 and NR3 subunits and the glutamate-binding module of the NR2A subunit have been expressed as soluble proteins, and their three-dimensional structure has been solved at atomic resolution by x-ray crystallography. This has revealed a common fold with amino acid-binding bacterial proteins and with the glutamate-binding module of AMPA-receptors and kainate-receptors.

Variants

GluN1

There are eight variants of the NR1 subunit produced by alternative splicing of GRIN1:^[8]

NR1-1a, NR1-1b; NR1-1a is the most abundantly expressed form.
NR1-2a, NR1-2b;
NR1-3a, NR1-3b;
NR1-4a, NR1-4b;

GluN2

NR2 subunit in vertebrates (left) and invertebrates (right). Ryan et al., 2008

While a single NR2 subunit is found in invertebrate organisms, four distinct isoforms of the NR2 subunit are expressed in vertebrates and are referred to with the nomenclature NR2A through D(coded by GRIN2A, GRIN2B, GRIN2C, GRIN2D). Strong evidence shows that the genes coding the NR2 subunits in vertebrates have undergone at least two rounds of gene duplication.^[9] They contain the binding-site for the neurotransmitter glutamate. More importantly, each NR2 subunit has a different intracellular C-terminal domain that can interact with different sets of signalling molecules.^[10] Unlike NR1 subunits, NR2 subunits are expressed differentially across various cell types and control the electrophysiological properties of the NMDA receptor. One particular subunit, NR2B, is mainly present in immature neurons and in extrasynaptic locations, and contains the binding-site for the selective inhibitor ifenprodil.

Whereas NR2B is predominant in the early postnatal brain, the number of NR2A subunits grows, and eventually NR2A subunits outnumber NR2B. This is called NR2B-NR2A developmental switch, and is notable because of the different kinetics each NR2 subunit lends to the receptor.^[11] For instance, greater ratios of the NR2B subunit leads to NMDA receptors which remain open longer compared to those with more NR2A.^[12] This may in part account for greater memory abilities in the immediate postnatal period compared to late in life, which is the principle behind genetically-altered 'doogie mice'.

There are three hypothetical models to describe this switch mechanism:

Dramatic increase in synaptic NR2A along with decrease in NR2B
Extrasynaptic displacement of NR2B away from the synapse with increase in NR2A
Increase of NR2A diluting the number of NR2B without the decrease of the latter.

The NR2B and NR2A subunits also have differential roles in mediating excitotoxic neuronal death.^[13] The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity.^[14] Disruption of the gene for NR2B in mice causes perinatal lethality, whereas the disruption of NR2A gene produces viable mice, although with impaired hippocampal plasticity.^[15] One study suggests that reelin may play a role in the NMDA receptor maturation by increasing the NR2B subunit mobility.^[16]

NR2B to NR2C switch

Granule cell precursors (GCPs) of the cerebellum, after undergoing symmetric cell division^[17] in the external granule-cell layer (EGL), migrate into the internal granule-cell layer (IGL) where they downregulate NR2B and activate NR2C, a process that is independent of neuregulin beta signaling through ErbB2 and ErbB4 receptors.^[18]

Ligands

Agonists

Activation of NMDA receptors requires binding of glutamate or aspartate (aspartate does not stimulate the receptors as strongly).^[19] In addition, NMDARs also require the binding of the co-agonist glycine for the efficient opening of the ion channel, which is a part of this receptor.

D-serine has also been found to co-agonize the NMDA receptor with even greater potency than glycine.^[20] D-serine is produced by serine racemase, and is enriched in the same areas as NMDA receptors. Removal of D-serine can block NMDA-mediated excitatory neurotransmission in many areas. Recently, it has been shown that D-serine can be released both by neurons and astrocytes to regulate NMDA receptors.

NMDA receptor (NMDAR)-mediated currents are directly related to membrane depolarization. NMDA agonists therefore exhibit fast Mg²⁺ unbinding kinetics, increasing channel open probability with depolarization. This property is fundamental to the role of the NMDA receptor in memory and learning, and it has been suggested that this channel is a biochemical substrate of Hebbian learning, where it can act as a coincidence detector for membrane depolarization and synaptic transmission.

Some known NMDA receptor agonists include:

Aminocyclopropanecarboxylic acid
D-Cycloserine
cis-2,3-Piperidinedicarboxylic acid
L-Aspartate
Quinolinate
Homocysterate
D-Serine
ACPL
L-Alanine

Partial agonists

N-Methyl-D-aspartic acid (NMDA)
3,5-dibromo-L-phenylalanine^[21]
GLYX-13
NRX-1074

Glycine-site NMDA receptor partial agonists, such as GLYX-13 and NRX-1074, are now viewed with great interest for the development of new drugs with antidepressant and analgesic effects without obvious psychotomimetic activities.^[22]

Antagonists

Antagonists of the NMDA receptor are used as anesthetics for animals and sometimes humans, and are often used as recreational drugs due to their hallucinogenic properties, in addition to their unique effects at elevated dosages such as dissociation. When certain NMDA receptor antagonists are given to rodents in large doses, they can cause a form of brain damage called Olney's lesions. NMDA receptor antagonists that have been shown to induce Olney's lesions include ketamine, phencyclidine, and dextrorphan (a metabolite of dextromethorphan), as well as some NMDA receptor antagonists used only in research environments. So far, the published research on Olney's lesions is inconclusive in its occurrence upon human or monkey brain tissues with respect to an increase in the presence of NMDA receptor antagonists.^[23]

Common agents in which NMDA receptor antagonism is the primary mechanism of action:

AP5
Conantokins
Dextromethorphan
Dexanabinol
Dizocilpine (MK-801)
Ketamine
Memantine
Nitrous oxide
Phencyclidine
Xenon

Some common agents in which weak NMDA receptor antagonism is a secondary or additional action include:

Amantadine^[24]
Atomoxetine^[25]
Dextropropoxyphene
Ethanol
Huperzine A
Ibogaine
Ketobemidone
Methadone – an opioid analgesic
Tramadol – an atypical analgesic

Kynurenic acid is an endogenous NMDA receptor antagonist.

Modulators

The NMDA receptor is modulated by a number of endogenous and exogenous compounds:^[26]

Mg²⁺ not only blocks the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive membrane potentials. Treatment with forms magnesium glycinate and magnesium taurinate has been used to produce rapid recovery from depression.^[27]

Na⁺, K⁺ and Ca²⁺ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors.

Zn²⁺ and Cu²⁺ generally block NMDA current activity in a noncompetitive and a voltage-independent manner. However zinc may potentiate or inhibit the current depending on the neural activity. (Zinc and Copper Influence Excitability of Rat Olfactory Bulb Neurons by Multiple Mechanisms|http://jn.physiology.org/content/86/4/1652.short)

Pb²⁺^[28] is a potent NMDAR antagonist. Presynaptic deficits resulting from Pb²⁺ exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling.

It has been demonstrated that polyamines do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate-mediated responses.

Aminoglycosides have been shown to have a similar effect to polyamines, and this may explain their neurotoxic effect.

The activity of NMDA receptors is also strikingly sensitive to the changes in H⁺ concentration, and partially inhibited by the ambient concentration of H⁺ under physiological conditions. ^[29] The level of inhibition by H⁺ is greatly reduced in receptors containing the NR1a subtype, which contains the positively charged insert Exon 5. The effect of this insert may be mimicked by positively charged polyamines and aminoglycosides, explaining their mode of action.

NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the so-called "redox modulatory site."^[30] Through this site, reductants dramatically enhance NMDA channel activity, whereas oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as glutathione, lipoic acid, and the essential nutrient pyrroloquinoline quinone.

Src kinase enhances NMDA receptor currents.^[31]

Reelin modulates NMDA function through Src family kinases and DAB1.^[32]significantly enhancing LTP in the hippocampus.

CDK5 regulates the amount of NR2B-containing NMDA receptors on the synaptic membrane, thus affecting synaptic plasticity.^[33]^[34]

Proteins of the major histocompatibility complex class I are endogenous negative regulators of NMDAR-mediated currents in the adult hippocampus,^[35] and are required for appropriate NMDAR-induced changes in AMPAR trafficking ^[35] and NMDAR-dependent synaptic plasticity and learning and memory.^[36]^[37]

Receptor modulation

The NMDA receptor is a non-specific cation channel that can allow the passage of Ca²⁺ and Na⁺ into the cell and K⁺ out of the cell. The excitatory postsynaptic potential (EPSP) produced by activation of an NMDA receptor increases the concentration of Ca²⁺ in the cell. The Ca²⁺ can in turn function as a second messenger in various signaling pathways. However, the NMDA receptor cation channel is blocked by Mg²⁺ at resting membrane potential. To unblock the channel, the postsynaptic cell must be depolarized.^[38]

Therefore, the NMDA receptor functions as a "molecular coincidence detector". Its ion channel opens only when the following two conditions are met simultaneously: glutamate is bound to the receptor, and the postsynaptic cell is depolarized (which removes the Mg²⁺ blocking the channel). This property of the NMDA receptor explains many aspects of long-term potentiation (LTP) and synaptic plasticity.^[39]

NMDA receptors are modulated by a number of endogenous and exogenous compounds and play a key role in a wide range of physiological (e.g., memory) and pathological processes (e.g., excitotoxicity).

Clinical significance

Memantine is approved by the U.S. F.D.A and the European Medicines Agency for treatment of moderate-to-severe Alzheimer's disease,^[40] and has now received a limited recommendation by the UK's National Institute for Health and Care Excellence for patients who fail other treatment options.^[41]

Cochlear NMDARs are the target of intense research to find pharmacological solutions to treat tinnitus. Recently, NMDARs were associated with a rare autoimmune disease, anti-NMDAR encephalitis, that usually occurs due to cross reactivity of antibodies produced by the immune system against ectopic brain tissues, such as those found in teratoma.

NMDAR modulators, including esketamine, GLYX-13, NRX-1074, and CERC-301, are under development for the treatment of mood disorders, including major depressive disorder and treatment-resistant depression.^[42] In addition, ketamine is already employed for this purpose as an off-label therapy in some clinics.^[43]^[44]

Compared to dopaminergic stimulants, phencyclidine can produce a wider range of symptoms that resemble schizophrenia in healthy volunteers, in what has led to the glutamate hypothesis of schizophrenia.^[45] Experiments in which rodents are treated with NMDA receptor antagonist are today the most common model when it comes to testing of novel schizophrenia therapies or exploring the exact mechanism of drugs already approved for treatment of schizophrenia.

External links

Media related to NMDA receptor at Wikimedia Commons
NMDA receptor pharmacology
Motor Discoordination Results from Combined Gene Disruption of the NMDA Receptor NR2A and NR2C Subunits, But Not from Single Disruption of the NR2A or NR2C Subunit
A schematic diagram summarizes three potential models for the switching of NR2A and NR2B subunits at developing synapses. - a figure from Liu et al., 2004^[46]
Drosophila NMDA receptor 1 - The Interactive Fly

References

^ Laube B, Hirai H, Sturgess M, Betz H, Kuhse J (1997). "Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit". Neuron 18 (3): 493–503. doi:10.1016/S0896-6273(00)81249-0. PMID 9115742.
^ Li F, Tsien JZ (2009). "Memory and the NMDA receptors". N. Engl. J. Med. 361 (3): 302–3. doi:10.1056/NEJMcibr0902052. PMC 3703758. PMID 19605837.
^ Dingledine R, Borges K, Bowie D, Traynelis SF (March 1999). "The glutamate receptor ion channels". Pharmacol. Rev. 51 (1): 7–61. PMID 10049997.
^ Liu Y, Zhang J (October 2000). "Recent development in NMDA receptors". Chin. Med. J. 113 (10): 948–56. PMID 11775847.
^ Cull-Candy S, Brickley S, Farrant M (June 2001). "NMDA receptor subunits: diversity, development and disease". Curr. Opin. Neurobiol. 11 (3): 327–35. doi:10.1016/S0959-4388(00)00215-4. PMID 11399431.
^ Paoletti P, Neyton J (February 2007). "NMDA receptor subunits: function and pharmacology". Curr Opin Pharmacol 7 (1): 39–47. doi:10.1016/j.coph.2006.08.011. PMID 17088105.
^ Kleckner NW, Dingledine R (August 1988). "Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes". Science 241 (4867): 835–7. doi:10.1126/science.2841759. PMID 2841759.
^ Stephenson FA (November 2006). "Structure and trafficking of NMDA and GABAA receptors". Biochem. Soc. Trans. 34 (Pt 5): 877–81. doi:10.1042/BST0340877. PMID 17052219.
^ Teng H. J., Cai W.S., Zhou L.L, Zhang J., Liu Q., Wang Y.Q., Dai W., Zhao M., Sun Z.S. et al. (2010). "Evolutionary Mode and Functional Divergence of Vertebrate NMDA Receptor Subunit 2 Genes". In Desalle, Robert. PLoS ONE 5 (10): e13342. doi:10.1371/journal.pone.0013342.
^ Ryan, T. J. & Grant, S. G. N. (2009) The origin and evolution of synapses (vol 10, pg 701, 2009). Nat Rev Neurosci 10, Doi 10.1038/Nrn2748
^ Liu XB, Murray KD, Jones EG (October 2004). "Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development". J. Neurosci. 24 (40): 8885–95. doi:10.1523/JNEUROSCI.2476-04.2004. PMID 15470155.
^ last, first (April 2000). "title". Scientific American.
^ Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT (March 2007). "NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo". J. Neurosci. 27 (11): 2846–57. doi:10.1523/JNEUROSCI.0116-07.2007. PMID 17360906.
^ Zhou M, Baudry M (March 2006). "Developmental changes in NMDA neurotoxicity reflect developmental changes in subunit composition of NMDA receptors". J. Neurosci. 26 (11): 2956–63. doi:10.1523/JNEUROSCI.4299-05.2006. PMID 16540573.
^ Sprengel R. et al. (1998). "Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo". Cell 92 (2): 279–289. doi:10.1016/S0092-8674(00)80921-6. PMID 9458051.
^ Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P (2007). "NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin". J. Neurosci. 27 (38): 10165–75. doi:10.1523/JNEUROSCI.1772-07.2007. PMID 17881522.
^ Espinosa JS, Luo LJ (March 2008). "Timing neurogenesis and differentiation: insights from quantitative clonal analyses of cerebellar granule cells". J. Neurosci. 28 (10): 2301–12. doi:10.1523/JNEUROSCI.5157-07.2008. PMC 2586640. PMID 18322077.
^ Gajendran N, Kapfhammer JP, Lain E, Canepari M, Vogt K, Wisden W,Brenner HR (February 2009). "Neuregulin Signaling Is Dispensable for NMDA- and GABAA-Receptor Expression in the Cerebellum In Vivo". J. Neurosci. 28 (10): 2301–12. doi:10.1523/JNEUROSCI.4303-08.2009. PMC 2586640. PMID 19244516.
^ Chen PE, Geballe MT, Stansfeld PJ, Johnston AR, Yuan H, Jacob AL, Snyder JP, Traynelis SF, Wyllie DJ (May 2005). "Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling". Mol. Pharmacol. 67 (5): 1470–84. doi:10.1124/mol.104.008185. PMID 15703381.
^ Wolosker H (Oct 2006). "D-serine regulation of NMDA receptor activity". Sci. STKE pe41 (356): 1–3. doi:10.1126/stke.3562006pe41. PMID 17033043.
^ Yarotskyy V, Glushakov AV, Sumners C, Gravenstein N, Dennis DM, Seubert CN, Martynyuk AE (May 2005). "Differential modulation of glutamatergic transmission by 3,5-dibromo-L-phenylalanine". Mol. Pharmacol. 67 (5): 1648–54. doi:10.1124/mol.104.005983. PMID 15687225.
^ J. Moskal, D. Leander, R. Burch (2010). Unlocking the Therapeutic Potential of the NMDA Receptor. Drug Discovery & Development News. Retrieved 19 December 2013.
^ Anderson C (2003-06-01). "The Bad News Isn't In: A Look at Dissociative-Induced Brain Damage and Cognitive Impairment". Erowid DXM Vaults : Health. Retrieved 2008-12-17.
^ "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy". ClinicalTrials.gov. 2005-09-01. Retrieved 2008-12-17.
^ "Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations". British Journal of Pharmacology. 2013-05-08. Retrieved 2010-03-02.
^ Huggins DJ, Grant GH (January 2005). "The function of the amino terminal domain in NMDA receptor modulation". J. Mol. Graph. Model. 23 (4): 381–8. doi:10.1016/j.jmgm.2004.11.006. PMID 15670959.
^ Eby GA, Eby KL (2006). "Rapid recovery from major depression using magnesium treatment". Medical hypotheses 67 (2): 362–70. doi:10.1016/j.mehy.2006.01.047. PMID 16542786.
^ Toxicol. Sci. 2010 116: 249–263; doi:10.1093/toxsci/kfq111
^ Traynelis, Stephen; Cull-Candy (May 24, 1990). "Stuart". Nature 345 (6273): 347-50. doi:10.1038/345347a0. PMID 1692970.
^ Aizenman E, Lipton SA, Loring RH (March 1989). "Selective modulation of NMDA responses by reduction and oxidation". Neuron 2 (3): 1257–63. doi:10.1016/0896-6273(89)90310-3. PMID 2696504.
^ Yu XM, Askalan R, Keil GJ, Salter MW (January 1997). "NMDA channel regulation by channel-associated protein tyrosine kinase Src". Science 275 (5300): 674–8. doi:10.1126/science.275.5300.674. PMID 9005855.
^ Chen Y, Beffert U, Ertunc M, Tang TS, Kavalali ET, Bezprozvanny I, Herz J (September 2005). "Reelin modulates NMDA receptor activity in cortical neurons". J. Neurosci. 25 (36): 8209–16. doi:10.1523/JNEUROSCI.1951-05.2005. PMID 16148228.
^ Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA (July 2007). "Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation". Nat. Neurosci. 10 (7): 880–6. doi:10.1038/nn1914. PMID 17529984.
^ Zhang S, Edelmann L, Liu J, Crandall JE, Morabito MA (January 2008). "Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors". J. Neurosci. 28 (2): 415–24. doi:10.1523/JNEUROSCI.1900-07.2008. PMID 18184784.
^ ^a ^b Fourgeaud L, Davenport CM, Tyler CM, Cheng TT, Spencer MB, Boulanger LM (December 2010). "MHC class I modulates NMDA receptor function and AMPA receptor trafficking". Proc Natl Acad Sci U S A 107 (51): 22278–83. doi:10.1073/pnas.0914064107. PMC 3009822. PMID 21135233.
^ Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ (December 2000). "Functional requirement for class I MHC in CNS development and plasticity". Science 290 (5499): 2155–9. doi:10.1126/science.290.5499.2155. PMC 2175035. PMID 11118151.
^ Nelson, PA; Sage, JR; Wood, SC; Davenport, CM; Anagnostaras, SG; Boulanger, LM (Sep 1, 2013). "MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression.". Learning & memory (Cold Spring Harbor, N.Y.) 20 (9): 505–17. doi:10.1101/lm.031351.113. PMID 23959708.
^ Purves, Dale; George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, Leonard E. White (2008). Neuroscience, 4th Ed.. Sinauer Associates. pp. 129–131. ISBN 978-0-87893-697-7. Cite uses deprecated parameters (help)
^ Purves, Dale; George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, Leonard E. White (2008). Neuroscience, 4th Ed.. Sinauer Associates. pp. 191–195. ISBN 978-0-87893-697-7. Cite uses deprecated parameters (help)
^ Mount C, Downton C (July 2006). "Alzheimer disease: progress or profit?". Nat Med. 12 (7): 780–4. doi:10.1038/nm0706-780. PMID 16829947.
^ NICE technology appraisal January 18, 2011 Azheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination
^ Wijesinghe, R (2014). "Emerging Therapies for Treatment Resistant Depression". Ment Health Clin 4 (5): 56. ISSN 2168-9709.
^ Linda Poon (2014). "Growing Evidence That A Party Drug Can Help Severe Depression". NPR.
^ Gary Stix (2014). "From Club to Clinic: Physicians Push Off-Label Ketamine as Rapid Depression Treatment". Scientific American.
^ Lisman JE, Coyle JT, Green RW, et al. (May 2008). "Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia". Trends in Neurosciences 31 (5): 234–42. doi:10.1016/j.tins.2008.02.005. PMC 2680493. PMID 18395805.
^ Liu XB, Murray KD, Jones EG (October 2004). "Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development". J. Neurosci. 24 (40): 8885–95. doi:10.1523/JNEUROSCI.2476-04.2004. PMID 15470155.

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 腫瘍随伴性および自己免疫性脳炎 paraneoplastic and autoimmune encephalitis
2. 認知症の治療 treatment of dementia
3. 小児に対する手術室外での鎮静処置に使用する薬剤 pharmacologic agents for pediatric procedural sedation outside of the operating room
4. 狂犬病の治療 treatment of rabies
5. 離人症性障害：疫学、病因、臨床症状、経過、および診断 depersonalization disorder epidemiology pathogenesis clinical manifestations course and diagnosis

English Journal

Inhibition of glutamate regulated calcium entry into leukemic megakaryoblasts reduces cell proliferation and supports differentiation.

Kamal T1, Green TN1, Morel-Kopp MC2, Ward CM2, McGregor AL3, McGlashan SR4, Bohlander SK1, Browett PJ5, Teague L6, During MJ7, Skerry TM8, Josefsson EC9, Kalev-Zylinska ML10.
Cellular signalling.Cell Signal.2015 Sep;27(9):1860-72. doi: 10.1016/j.cellsig.2015.05.004. Epub 2015 May 14.
Human megakaryocytes release glutamate and express glutamate-gated Ca(2+)-permeable N-methyl-D-aspartate receptors (NMDARs) that support megakaryocytic maturation. While deregulated glutamate pathways impact oncogenicity in some cancers, the role of glutamate and NMDARs in megakaryocytic malignancie
PMID 25982509

Comparative ventilatory strategies of acclimated rats and burrowing plateau pika (Ochotona curzoniae) in response to hypoxic-hypercapnia.

Pichon A1, Voituron N2, Bai Z3, Jeton F2, Tana W3, Marchant D4, Jin G3, Richalet JP2, Ge RL3.
Comparative biochemistry and physiology. Part A, Molecular & integrative physiology.Comp Biochem Physiol A Mol Integr Physiol.2015 Sep;187:103-10. doi: 10.1016/j.cbpa.2015.05.004. Epub 2015 May 16.
The objective of this study was to compare the different ventilatory strategies that help in coping with hypoxic-hypercapnia environment among two species: use acclimated rats and plateau pikas (Ochotona curzoniae) that live in Tibetan plateaus, and have been well adjusted to high altitude. Arterial
PMID 25988712

Effect of salinity changes on olfactory memory-related genes and hormones in adult chum salmon Oncorhynchus keta.

Kim NN1, Choi YJ1, Lim SG2, Jeong M2, Jin DH3, Choi CY4.
Comparative biochemistry and physiology. Part A, Molecular & integrative physiology.Comp Biochem Physiol A Mol Integr Physiol.2015 Sep;187:40-7. doi: 10.1016/j.cbpa.2015.04.011. Epub 2015 Apr 29.
Studies of memory formation have recently concentrated on the possible role of N-methyl-d-aspartate receptors (NRs). We examined changes in the expression of three NRs (NR1, NR2B, and NR2C), olfactory receptor (OR), and adrenocorticotropic hormone (ACTH) in chum salmon Oncorhynchus keta using quanti
PMID 25933936