Extrasynaptic NMDA receptor explained

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]

Notes and References

  1. Tovar. Kenneth R.. Westbrook. Gary L.. 2002-04-11. Mobile NMDA receptors at hippocampal synapses. Neuron. 34. 2. 255–264. 0896-6273. 11970867. 10.1016/s0896-6273(02)00658-x. free.
  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. 10.1016/j.neuroscience.2010.01.022. 1873-7544. 2840201. 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. 10.1038/nn835. 1097-6256. 11953750. 659716.
  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. 10.1038/nm.2056. 1546-170X. 2789858. 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. 10.1016/j.neuron.2010.01.008. 1097-4199. 20152125. free.
  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. 10.1073/pnas.1306832110. 1091-6490. 3704025. 23776240. 2013PNAS..110E2518T . free.
  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. 10.1038/nrn2911. 1471-0048. 2948541. 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. 10.1016/j.neuron.2014.03.030. 1097-4199. 24742457. free.
  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. eaay3302. 10.1126/science.aay3302. 1095-9203. 33033186. 222210921.
  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. eaay3302. 10.1126/science.aay3302. 1095-9203. 33033186. 222210921.
  11. Web site: New Class of Highly Effective Inhibitors Protects against Neurodegeneration – Heidelberg University. 2020-10-29. www.uni-heidelberg.de.

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