N-Methyl-D-aspartic acid explained

N-methyl--aspartic acid or N-methyl--aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors (such as those for AMPA and kainate). NMDA receptors are particularly important when they become overactive during, for example, withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures.

Biological function

In 1962, J.C. Watkins reported synthesizing NMDA, an isomer of the previously known N-Methyl--aspartic-acid.[1] [2] NMDA is a water-soluble -alpha-amino acid — an aspartic acid derivative with an N-methyl substituent and -configuration — found across Chordates from lancelets to mammals.[3] [4] At homeostatic levels NMDA plays an essential role as a neurotransmitter and neuroendocrine regulator.[5] At increased but sub–toxic levels NMDA becomes neuro-protective. In excessive amounts NMDA is an excitotoxin. Behavioral neuroscience research utilizes NMDA excitotoxicity to induce lesions in specific regions of an animal subject's brain or spinal cord to study behavioral changes.[6]

The mechanism of action for the NMDA receptor is a specific agonist binding to its NR2 subunits, and then a non-specific cation channel is opened, which can allow the passage of Ca2+ and Na+ into the cell and K+ out of the cell. Therefore, NMDA receptors will only open if glutamate is in the synapse and concurrently the postsynaptic membrane is already depolarized - acting as coincidence detectors at the neuronal level.[7] The excitatory postsynaptic potential (EPSP) produced by activation of an NMDA receptor also increases the concentration of Ca2+ in the cell. The Ca2+ can in turn function as a second messenger in various signaling pathways.[8] [9] [10] [11] This process is modulated by a number of endogenous and exogenous compounds and plays a key role in a wide range of physiological (such as memory) and pathological processes (such as excitotoxicity).

Antagonists

See main article: NMDA receptor antagonist.

Examples of antagonists, or more appropriately named receptor channel blockers, of the NMDA receptor are APV, amantadine, dextromethorphan (DXM), ketamine, magnesium,[12] tiletamine, phencyclidine (PCP), riluzole, memantine, methoxetamine (MXE), methoxphenidine (MXP) and kynurenic acid. While dizocilpine is generally considered to be the prototypical NMDA receptor blocker and is the most common agent used in research, animal studies have demonstrated some amount of neurotoxicity, which may or may not also occur in humans. These compounds are commonly referred to as NMDA receptor antagonists.

See also

Notes and References

  1. 10.1021/jm01241a010. 1520-4804. 5. 6. 1187–1199. Watkins. J. C.. The synthesis of some acidic amino acids possessing neuropharmacological activity. Journal of Medicinal and Pharmaceutical Chemistry. November 1962. 14056452.
  2. 10.1111/j.1471-4159.1960.tb13458.x. 1471-4159. 6. 2. 117–141. Curtis. D. R.. Watkins. J. C.. The excitation and depression of spinal neurones by structurally related amino acids. Journal of Neurochemistry. September 1960. 13718948. 37212083.
  3. 10.1016/S0378-4347(99)00089-4. 0378-4347. 728. 1. 41–47. Todoroki. Natsumi. Shibata. Kimihiko. Yamada. Takahiro. Kera. Yoshio. Yamada. Ryo-hei. Determination of N-methyl--aspartic in tissues of bivalves by high-performance liquid chromatography. Journal of Chromatography B: Biomedical Sciences and Applications. May 1999. 10379655.
  4. 10.1016/S0003-2697(02)00326-3. 0003-2697. 308. 1. 42–51. D'Aniello. Antimo. De Simone. Antonella. Spinelli. Patrizia. D'Aniello. Salvatore. Branno. Margherita. Aniello. Francesco. Rios. Jeannette. Tsesarskaja. Mara. Fisher. George. A specific enzymatic high-performance liquid chromatography method to determine N-methyl--aspartic acid in biological tissues. Analytical Biochemistry. September 2002. 12234462.
  5. 10.1016/S0003-2697(02)00326-3. 0003-2697. 308. 1. 42–51. D'Aniello. Antimo. De Simone. Antonella. Spinelli. Patrizia. D'Aniello. Salvatore. Branno. Margherita. Aniello. Francesco. Rios. Jeannette. Tsesarskaja. Mara. Fisher. George. A specific enzymatic high-performance liquid chromatography method to determine N-methyl--aspartic acid in biological tissues. Analytical Biochemistry. 2020-05-02. 2002-09-01. 12234462.
  6. 10.1016/0006-8993(96)00202-8. 0006-8993. 722. 1–2. 109–117. Johnson. Patricia I.. Parente. Mary Ann. Stellar. James R.. NMDA-induced lesions of the nucleus accumbens or the ventral pallidum increase the rewarding efficacy of food to deprived rats. Brain Research. May 1996. 8813355. 23002111.
  7. Buhusi . CV . Oprisan . SA . Buhusi . M . Clocks within Clocks: Timing by Coincidence Detection . Current Opinion in Behavioral Sciences. April 2016 . 8 . 207–213 . 10.1016/j.cobeha.2016.02.024 . 27004236 . 4797640 . free .
  8. Dingledine. R. Borges K. The glutamate receptor ion channels. Pharmacol. Rev.. Mar 1999. 51. 1. 7–61. 10049997.
  9. Liu. Y. Zhang J. Recent development in NMDA receptors. Chin Med J (Engl). Oct 2000. 113. 10. 948–956. 11775847.
  10. Cull-Candy. S. Brickley S. NMDA receptor subunits: diversity, development and disease. Current Opinion in Neurobiology. Jun 2001. 11. 3. 327–335. 11399431. 10.1016/S0959-4388(00)00215-4. 11929361.
  11. Paoletti. P. Neyton J. NMDA receptor subunits: function and pharmacology. Current Opinion in Pharmacology. Feb 2007. 7. 1. 39–47. 17088105. 10.1016/j.coph.2006.08.011.
  12. Murck. H.. 2002-01-01. Magnesium and Affective Disorders. Nutritional Neuroscience. 5. 6. 375–389. 10.1080/1028415021000039194. 1028-415X. 12509067. 28550919.

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