From Wikipedia, the free encyclopedia
Extrasynaptic NMDA receptors are glutamate-gated
neurotransmitter receptors that are localized to non-synaptic sites on the
neuron al
cell surface .
[1]
[2] In contrast to synaptic NMDA receptors that promote
acquired neuroprotection and
synaptic plasticity , extrasynaptic NMDA receptors are coupled to activation of death-signaling pathways.
[3] Extrasynaptic NMDA receptors are responsible for initiating
excitotoxicity and have been implicated in the etiology of
neurodegenerative diseases , including
stroke ,
Huntington’s disease ,
Alzheimer’s disease , and
amyotrophic lateral sclerosis (ALS).
[4]
[5]
[6]
[7]
[8]
Extrasynaptic NMDA receptors form a death signaling complex with the transient receptor potential cation channel subfamily M member 4 (TRPM4). The NMDAR/TRPM4 complex is considered central to glutamate excitotoxicity.
[9] NMDAR/TRPM4 interaction interface inhibitors (also known as 'interface inhibitors') disrupt the NMDAR/TRPM4 complex thereby detoxifying extrasynaptic NMDA receptors. In mouse disease models, interface inhibitors protect against stroke induced brain damage and retinal ganglion cell degeneration.
[10]
[11]
References
^ Tovar, Kenneth R.; Westbrook, Gary L. (2002-04-11).
"Mobile NMDA receptors at hippocampal synapses" . Neuron . 34 (2): 255–264.
doi :
10.1016/s0896-6273(02)00658-x .
ISSN
0896-6273 .
PMID
11970867 .
^ Petralia, R. S.; Wang, Y. X.; Hua, F.; Yi, Z.; Zhou, A.; Ge, L.; Stephenson, F. A.; Wenthold, R. J. (2010-04-28).
"Organization of NMDA receptors at extrasynaptic locations" . Neuroscience . 167 (1): 68–87.
doi :
10.1016/j.neuroscience.2010.01.022 .
ISSN
1873-7544 .
PMC
2840201 .
PMID
20096331 .
^ Hardingham, G. E.; Fukunaga, Y.; Bading, H. (2002-05-01). "Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways". Nature Neuroscience . 5 (5): 405–414.
doi :
10.1038/nn835 .
ISSN
1097-6256 .
PMID
11953750 .
S2CID
659716 .
^ Okamoto, Shu-ichi; Pouladi, Mahmoud A.; Talantova, Maria; Yao, Dongdong; Xia, Peng; Ehrnhoefer, Dagmar E.; Zaidi, Rameez; Clemente, Arjay; Kaul, Marcus (2009-12-01).
"Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin" . Nature Medicine . 15 (12): 1407–1413.
doi :
10.1038/nm.2056 .
ISSN
1546-170X .
PMC
2789858 .
PMID
19915593 .
^ Milnerwood, Austen J.; Gladding, Clare M.; Pouladi, Mahmoud A.; Kaufman, Alexandra M.; Hines, Rochelle M.; Boyd, Jamie D.; Ko, Rebecca W. Y.; Vasuta, Oana C.; Graham, Rona K. (2010-01-28).
"Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice" . Neuron . 65 (2): 178–190.
doi :
10.1016/j.neuron.2010.01.008 .
ISSN
1097-4199 .
PMID
20152125 .
^ Talantova, Maria; Sanz-Blasco, Sara; Zhang, Xiaofei; Xia, Peng; Akhtar, Mohd Waseem; Okamoto, Shu-ichi; Dziewczapolski, Gustavo; Nakamura, Tomohiro; Cao, Gang (2013-07-02).
"Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss" . Proceedings of the National Academy of Sciences of the United States of America . 110 (27): E2518–2527.
Bibcode :
2013PNAS..110E2518T .
doi :
10.1073/pnas.1306832110 .
ISSN
1091-6490 .
PMC
3704025 .
PMID
23776240 .
^ Hardingham, Giles E.; Bading, Hilmar (2010-10-01).
"Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders" . Nature Reviews. Neuroscience . 11 (10): 682–696.
doi :
10.1038/nrn2911 .
ISSN
1471-0048 .
PMC
2948541 .
PMID
20842175 .
^ Parsons, Matthew P.; Raymond, Lynn A. (2014-04-16).
"Extrasynaptic NMDA receptor involvement in central nervous system disorders" . Neuron . 82 (2): 279–293.
doi :
10.1016/j.neuron.2014.03.030 .
ISSN
1097-4199 .
PMID
24742457 .
^ Yan, Jing; Bengtson, C. Peter; Buchthal, Bettina; Hagenston, Anna M.; Bading, Hilmar (9 October 2020).
"Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants" . Science . 370 (6513): eaay3302.
doi :
10.1126/science.aay3302 .
ISSN
1095-9203 .
PMID
33033186 .
S2CID
222210921 .
^ Yan, Jing; Bengtson, C. Peter; Buchthal, Bettina; Hagenston, Anna M.; Bading, Hilmar (9 October 2020).
"Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants" . Science . 370 (6513): eaay3302.
doi :
10.1126/science.aay3302 .
ISSN
1095-9203 .
PMID
33033186 .
S2CID
222210921 .
^
"New Class of Highly Effective Inhibitors Protects against Neurodegeneration – Heidelberg University" . www.uni-heidelberg.de . Retrieved 2020-10-29 .