Research Breakdown on NMDA Neurotransmission
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NMDA receptors are one of the subsets of glutaminergic receptors, involved in mediating the effects of the main stimulatory neurotransmitter glutamate. NMDA receptors are also responsive to D-Aspartic Acid and its methylated form, which is N-methyl-D-Aspartic Acid (NMDA for short).
It is one of the more well researched glutaminergic receptors, alongside AMPA receptors and Kainate receptors. Beyond those three, there are a series of eight metabotropic glutamate receptors (mGluR1-8) which are G-protein coupled receptors.
When activated, NMDA receptors cause calcium influx into a neuron and increase its excitability.
The NMDA receptor is one of the receptors that mediates the effects of the main excitatory amino acid, glutamate. It is also selectively responsive to D-aspartic acid and named after it'e methylated form (N-methyl-D-aspartic acid or NMDA)
The NMDA receptor is known to have a glycine-binding site, which responds to glycinergic compounds with high affinity and subsequently alters the affinity of the NMDA receptor towards agonists. Due to this, activity at the glycine binding site is seen as supportive of NMDA neurotransmission and ligands that bind here are known as co-agonists.
Although the binding site is named after Glycine, which was the first agonist to be discovered to affect this site (hence the name), it was later discovered that D-serine is more biologically relevant at this site.
The glycine binding site positively modulates NMDA receptor activity, and glycincergic compounds can support NMDA neurotransmission
Synaptic receptors induce primarily nuclear Ca2+ signaling and are seen as neuroprotective, and are classically defined as functional receptors activated by glutmate during low frequency synaptic events.
Extrasynaptic receptors are those that mediate excitotoxic cell death. These consist of approximately one third of receptors in immature cells and increase with maturation. Approximately a quarter of extrasynaptic receptors are known as perisynaptic (within 100nM of the post-synaptic density).
NMDA receptors can be located on the synapse, or they can be located off the synapse (perisynaptic or extrasynaptic). Depending on the location of the receptor, they appear to have differential effects on the neuron
In general, COX2 appears to be involved in NMDA excitotoxicity and its pharmacological inhibition is able to reduce NMDA-mediated cell death in neurons. This neuroprotection can be reversed by the arachidonic acid prostaglandins PGE2 and since activation of the NMDA receptors has elsewhere been linked to an increase in COX2 mRNA and arachidonic acid metabolism which correlates with neurotoxicity it seems that excessive COX2 activity (from excessive NMDA activation) can cause prostaglandin-dependent neurotoxicity.
Mice completely lacking COX2, however, appear to have enhanced seizure threshold.
COX2 expression has differential effects on NMDA induced excitotoxicity, and while it is inhernetly protective it can mediate excitotoxic cell death when it is overexpressed
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