Iberoamerican Journal of Medicine
https://iberoamjmed.com/article/doi/10.5281/zenodo.3964576
Iberoamerican Journal of Medicine
Review

NMDA Receptors Subunits, Medical Conditions Involved in, and Their Roles as Drug Targets

Mohamed Omer

Downloads: 0
Views: 1155

Abstract

In the 1960s, Jeff Watkins and colleagues discovered N-methyl-d-aspartate (NMDA) receptors, and since then, it has been a pharmacodynamic target for many neurological and psychiatric drugs. NMDA is a glutamate receptor and ion channel protein located in nerve cells. There are many subunits for the NMDA receptor. They are all working together in a harmonic pattern to regulate the calcium permeability and the voltage-dependent sensitivity to magnesium influenced by the binding of glutamate as a neurotransmitter. In this paper, a light will be shed on glutamate ionotropic receptor NMDA subunits. There are several names for the GRIN gene, such as GluN. It is proven that GRIN has a significant influence on memory and learning abilities. Interestingly, part of how GRIN executes its function by interacting with other receptors. For example, GRIN counteracts the role of the cAMP response element-binding protein (CREP) receptor, while its function modulated by dopamine D1 receptors. Therefore, Hypo-functioning and mutation of this gene play a pivotal role in developing neurodevelopmental disorders wither it was with or without hyperkinetic movements and with and without seizures, besides several psychotic disorders such as schizophrenia. Hence, NMDA receptors subunits have been a target for therapeutic development for the last years. With the advancements in the genetic and genomic science, investigators are trying to find the alternative splicing of GRIN, understanding location and the distribution of NMDA subunits with deeper lucidity than it is currently. However, that is faced by some challenges. Modifying the NMDA receptor subunits to treat one condition can lead to potential harm effect in another condition because, sometimes, NMDA works complicatedly inversely with many other receptors and neurotransmitters, which will have an impact on the investigators to find the appropriate way to cause no harm.

Keywords

Neuropathology; Psychiatry; Pharmacology

References

1. Blanke ML, Van Dongen AMJ. Activation Mechanisms of the NMDA Receptor. In: Van Dongen AM, editors. Biology of the NMDA Receptor. Boca Raton (Florida): CRC Press/Taylor & Francis; 2009.
2. Lee CH, Lü W, Michel JC, Goehring A, Du J, Song X, et al. NMDA receptor structures reveal subunit arrangement and pore architecture. Nature. 2014;511(7508):191-7. doi: 10.1038/nature13548.
3. Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol. 2001;11(3):327-35. doi: 10.1016/s0959-4388(00)00215-4.
4. Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013;14(6):383-400. doi: 10.1038/nrn3504.
5. HUGO Gene Nomenclature Committee. Glutamate ionotropic receptor NMDA type subunits (GRIN). Available from: https://www.genenames.org/data/genegroup/#!/group/1201.
6. Fernandes HB, Raymond LA. NMDA Receptors and Huntington’s Disease. In: Van Dongen AM, editors. Biology of the NMDA Receptor. Boca Raton (Florida): CRC Press/Taylor & Francis; 2009.
7. Köhr G. NMDA receptor function: subunit composition versus spatial distribution. Cell Tissue Res. 2006;326(2):439-46. doi: 10.1007/s00441-006-0273-6.
8. Hallett PJ, Dunah AW, Ravenscroft P, Zhou S, Bezard E, Crossman AR, et al. Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Neuropharmacology. 2005;48(4):503-16. doi: 10.1016/j.neuropharm.2004.11.008.
9. Jiménez-Sánchez L, Campa L, Auberson YP, Adell A. The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression. Neuropsychopharmacology. 2014;39(11):2673-2680. doi: 10.1038/npp.2014.123.
10. Sceniak MP, Fedder KN, Wang Q, Droubi S, Babcock K, Patwardhan S, et al. An autism-associated mutation in GluN2B prevents NMDA receptor trafficking and interferes with dendrite growth. J Cell Sci. 2019;132(20):jcs232892. doi: 10.1242/jcs.232892.
11. Yuan H, Myers SJ, Wells G, Nicholson KL, Swanger SA, Lyuboslavsky P, et al. Context-dependent GluN2B-selective inhibitors of NMDA receptor function are neuroprotective with minimal side effects. Neuron. 2015;85(6):1305-18. doi: 10.1016/j.neuron.2015.02.008.
12. Zhou HY, Chen SR, Pan HL. Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain. Expert Rev Clin Pharmacol. 2011;4(3):379-88. doi: 10.1586/ecp.11.17.
13. Bond M, Rogers G, Peters J, Anderson R, Hoyle M, Miners A, et al. The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of Technology Appraisal No. 111): a systematic review and economic model. Health Technol Assess. 2012;16(21):1-470. doi: 10.3310/hta16210.
14. Gogas KR. Glutamate-based therapeutic approaches: NR2B receptor antagonists. Curr Opin Pharmacol. 2006;6(1):68-74. doi: 10.1016/j.coph.2005.11.001.
15. Dang YH, Ma XC, Zhang JC, Ren Q, Wu J, Gao CG, et al. Targeting of NMDA receptors in the treatment of major depression. Curr Pharm Des. 2014;20(32):5151-9. doi: 10.2174/1381612819666140110120435.
16. Hashimoto K. Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opin Ther Targets. 2014;18(9):1049-63. doi: 10.1517/14728222.2014.934225.


Submitted date:
06/27/2020

Reviewed date:
07/27/2020

Accepted date:
07/28/2020

Publication date:
07/28/2020

5f205d9c0e88255924dc6779 iberoamericanjm Articles
Links & Downloads

Iberoam J Med

Share this page
Page Sections