D-serine, the D-stereoisomer of serine, synthesized in the brain by serine racemase from its L-stereoisomer is considered a co-agonist I co-activator of glutamatergic N-methyl-0-aspartate receptors (NMDARs). However, this action of D-serine seems exclusive to di-heteromeric NMOARs containing subunits GluN1 and GluN2.
We have determined that D-serine works as a potent antagonist I inhibitor of GluN3-containing triheteromeric NMDARs that were discovered in our laboratory recently and found to exist in various regions of the brain. The discovery of this seemingly opposite effect on NMDARS has many therapeutic and non-therapeutic advantages including, but not restricted to, the following:
1. D-serine, unlike other NMOAR antagonists,may be well-tolerated in the brain, because it is naturally synthesized in the brain
2. D-serine's effect seems to be subunit specific (affecting only NMDARs that contain GluN3A or GluN3B whether they be di- or triheteromeric) making it amenable for targeted therapeutics (not all NMDARs would be affected by it in this way)
3. D-serine's antagonism of GluN3-containing triheteromeric NMDARs may be important because these receptors appear significantly more permeable 1 selective for calcium, a potent excitotoxicant that underlies cell death under a number of scenarios including epilepsy. Hence blocking these receptors specifically may aid in averting underlying pathology
4. D-serine can be used as a tool in basic research for identifying the expression of and determining the location of GluN3-containing triheteromeric NMDARs in the brain
