Extrasynaptic NMDA receptor

Extrasynaptic NMDA receptors are glutamate-gated neurotransmitter receptors that are localized to non-synaptic sites on the neuronal 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
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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. doi:10.1073/pnas.1306832110. ISSN 1091-6490. PMC 3704025. PMID 23776240.
  7. 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.
  8. 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.
  9. 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). doi:10.1126/science.aay3302. ISSN 1095-9203. PMID 33033186.
  10. 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). doi:10.1126/science.aay3302. ISSN 1095-9203. PMID 33033186.
  11. "New Class of Highly Effective Inhibitors Protects against Neurodegeneration – Heidelberg University". www.uni-heidelberg.de. Retrieved 2020-10-29.
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