Glycine binding appears to be an absolute requirement for NMDA channel activation. Studies of the NMDA receptor/channel complex at the molecular level indicate that binding of two glycines and two glutamate molecules is required for channel activation.
- See also D-Serine
- Synthesis of Glutamate Co-transmitter Glycine
- Glycine is not known to be synthesized by glutamate neurons, so glutamate neurons must acquire the glycine they need for their NMDA receptors from glycine neurons or from glial cells (Figure 1).3,7,8,10 Glycine neurons release glycine. However, they contribute only a small amount of glycine to glutamate synapses, since glycine is unable to diffuse far from neighboring glycine neurons because the glycine they release is taken back up into those neurons by a type of glycine reuptake pump known as the type-2 glycine transporter (Figure 1).
- Thus, neighboring glial cells are thought to be the source of most of the glycine available for glutamate synapses. Glycine itself can be taken up into glial cells either by a type-1 glycine transporter (GLY-T1) or by a glial specific neutral amino acid transporter (Figure 1).10,13-17 Glycine is released into glutamate synapses from glial cells by riding on a reversed GLY-T1 transporter (Figure 1).10 Once outside, glycine can re-enter the glial cell by riding on an inwardly directed GLY-T1, which functions as a reuptake pump and is the main mechanism responsible for terminating the action of synaptic glycine (Figure 1).10
- Glycine can also be synthesized from the amino acid L-serine, which is transported into the glial cell by an L-serine transporter, and then converted from L-serine into glycine by the glial enzyme serine hydroxy methyl transferase (Figure 1).10 This enzyme functions in both directions, either converting L-serine into glycine or glycine into L-serine.10
- Synthesis of Glutamate Co-transmitter D-serine
- D-serine is unusual in that it is a D-amino acid, whereas the 20 known essential amino acids are all L-amino acids, including D-serine’s mirror image amino acid L-serine.3,7,8,10 It just so happens that D-serine has a high affinity for the glycine site on NMDA receptors, and that glial cells are equipped with an enzyme that can convert regular L-serine into the neurotransmitting amino acid D-serine by means of an enzyme that can go back and forth between D- and L-serine (D-serine racemase) (Figure 2). Thus, D-serine can be derived from glycine or from L-serine, both of which can be transported into glial cells by their own transporters, and then glycine converted to L-serine by serine hydroxy methyl transferase, and finally L-serine converted into D-serine by the enzyme D-serine racemase (Figure 2). D-serine’s actions are not only terminated by synaptic reuptake via the inwardly acting glial serine transporter but also by an enzyme D-amino acid oxidase that converts D-serine into hydroxy-pyruvate (Figure 2).
- Targeting Glycine Modulation of NMDA Receptors
- Glycine Agonists
- Agonists at the glycine site of NMDA receptors include the naturally occurring amino acids glycine and D-serine (Figure 3).3,5,7,8,10,15-19 An analogue of D-serine, called D-cycloserine is also active at the glycine co-agonist site of NMDA receptors. All of these agents have been tested in schizophrenia with evidence that they can reduce negative and/or cognitive symptoms.5,7,8,10-19 Further testing of these naturally occurring agents is in progress and synthetic agonists with greater potency are in discovery.
<references> 8. Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol. 2006;26:365-384. 9. Stahl SM. Beyond the dopamine hypothesis to the NMDA receptor hypofunction hypothesis of schizophrenia. CNS Spectr. 2007;12:265-268. 10. Millan MJ. N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology. 2005;179:30-53. 11. Betz H, Gomeza J, Armsen W, Scholze P, Eulenburg V. Glycine transporters: essential regulators of synaptic transmission. Biochem Soc Trans. 2006;34(pt 1):55-58. 12. Long KD, Mastropaolo J, Rosse RB, Manaye KF, Deutsch SI. Modulatory effects of d-serine and sarcosine on NMDA receptor-mediated neurotransmission are apparent after stress in the genetically inbred BALB/c mouse strain. Brain Res Bull. 2006;69:626-630. 13. Harsing LG Jr, Juranyi Z, Gacsalyi Tapolcsanyi P, Czompa A, Matyus P. Glycine transporter type-1 and its inhibitors. Curr Med Chem. 2006;13:1017-1044. 14. Sur C, Kinney GG. The therapeutic potential of glycine transporter-1 inhibitors. Expert Opin Investig Drugs. 2004;13:515-521. 15. Javitt DC. Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry. 2006;19:151-157. 16. Coyle JT, Tsai G. The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology. 2004;174:32-28. 17. Heresco-Levy U. Glutamatergic neurotransmission modulators as emerging new drugs for schizophrenia. Expert Opin Emerg Drugs. 2005;10:827-844. 18. Heresco-Levy U, Javitt DC, Ebstein R, et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry. 2005;57:577-585. 19. Lane HY, Chang YC, Liu YC, Chiu, CC, Tsai GE. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized double blind placebo-controlled study. Arch Gen Psychiatry. 2005;62:1196-1204. 20. Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter 1 inhibitor, N-methylglycine (sarcosine) added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 2004;55:452-456.