pheochromo
Greenlighter
- Joined
- Apr 12, 2013
- Messages
- 1
The NMDA receptor is composed of 2 subunits of NR1 and 2 subunits of NR2. NR2 contains the glutamate analog binding site (e.g. glutamate, aspartate, N-Methyl-D-
aspartate, etc.) and comes in four isoforms (NR2A-D), each with a distinct profile of affinities for the various glutamate analogs.
NR1 also comes in multiple isoforms, and likewise they have different affinities for different compounds (glycine, D-serine, etc.)
Which of the various NR1 and NR2 subunits combine to form the final NMDA receptor will determine its properties (preffered activators, degree of voltage dependance)
and location (tissue type, synaptic or extrasynaptic).
For the NMDA channel to open, both NR1 and NR2 must be activated, as well as the removal of the magnesium ion which blocks the channel pore (voltage dependant
process). All the above compounds are agonists. NMDA receptor antagonists can target and compete with agonists for the specific subunit sites (competative inhibition).
They can bind some other location on the receptor and prevent its normal function (non-competative inhibition). Or they can block the channel pore like magnesium
(uncompetative inhibition).
CrimpJiggler: If the NMDA antagonist is competative for the glycine site, it would prevent/displace glycine from binding NMDAR, leaving it to interact with other
glycine receptors. Otherwise if it is another type of antagonist, glycine might still bind the NMDA receptor, but won't activate it, lowering the amount of glycine
available for other glycine receptors. This explains why NMDA antagonists are considered neuroprotective and anti-excitotoxic.
Also, uncompetative "pore blocker" antagonists require the channel to first open in order to get in and block it. This means both co-agonists must be present to
activate the NMDA receptor. Arylcyclohexylamines (ketamine, mxe) bind the allosteric PCP site and are non-competitive, so they do not need the receptor to be activated
first to work. Interestingly however, this "PCP" site is deep within the NMDA receptor, right alongside the channel (close to Mg ion), and so NMDA receptor activation and
opening enhances the antagonistic action of these drugs.
gladiolus:
>> This would explain why predosing glycine/glutamate results in apparent potentiation of mxe
sekio: "except glycine which normally exists as a charged zwitterion has trouble crossing the BBB"
>> This is true for simple diffusion, however there exist active transport mechanisms by which glycine and other amino acids can cross the BBB. (e.g. Transport system
ASC)
CrimpJiggler: "cation channels which, when activated, let an influx of sodium, potassium and calcium ions"
>> Unlike the other ions, potassium concentration is higher inside the cell than outside, so opening of non-specific cation channels would cause potassium outflux. But
along with sodium and calcium influx, the net effect is depolarization.
endotropic: "their data argues that NMDA voltage dependence is independent of magnesium."
>> Voltage dependant block of NMDARs by Mg is still very much a factor. This paper simply describes an additional voltage dependant conformational change in subunit
NR2B which contributes to channel opening. This is relevent only to NMDA receptors that incorporate NR2B. NR1/2A for example would not see this effect.
aspartate, etc.) and comes in four isoforms (NR2A-D), each with a distinct profile of affinities for the various glutamate analogs.
NR1 also comes in multiple isoforms, and likewise they have different affinities for different compounds (glycine, D-serine, etc.)
Which of the various NR1 and NR2 subunits combine to form the final NMDA receptor will determine its properties (preffered activators, degree of voltage dependance)
and location (tissue type, synaptic or extrasynaptic).
For the NMDA channel to open, both NR1 and NR2 must be activated, as well as the removal of the magnesium ion which blocks the channel pore (voltage dependant
process). All the above compounds are agonists. NMDA receptor antagonists can target and compete with agonists for the specific subunit sites (competative inhibition).
They can bind some other location on the receptor and prevent its normal function (non-competative inhibition). Or they can block the channel pore like magnesium
(uncompetative inhibition).
CrimpJiggler: If the NMDA antagonist is competative for the glycine site, it would prevent/displace glycine from binding NMDAR, leaving it to interact with other
glycine receptors. Otherwise if it is another type of antagonist, glycine might still bind the NMDA receptor, but won't activate it, lowering the amount of glycine
available for other glycine receptors. This explains why NMDA antagonists are considered neuroprotective and anti-excitotoxic.
Also, uncompetative "pore blocker" antagonists require the channel to first open in order to get in and block it. This means both co-agonists must be present to
activate the NMDA receptor. Arylcyclohexylamines (ketamine, mxe) bind the allosteric PCP site and are non-competitive, so they do not need the receptor to be activated
first to work. Interestingly however, this "PCP" site is deep within the NMDA receptor, right alongside the channel (close to Mg ion), and so NMDA receptor activation and
opening enhances the antagonistic action of these drugs.
gladiolus:
>> This would explain why predosing glycine/glutamate results in apparent potentiation of mxe
sekio: "except glycine which normally exists as a charged zwitterion has trouble crossing the BBB"
>> This is true for simple diffusion, however there exist active transport mechanisms by which glycine and other amino acids can cross the BBB. (e.g. Transport system
ASC)
CrimpJiggler: "cation channels which, when activated, let an influx of sodium, potassium and calcium ions"
>> Unlike the other ions, potassium concentration is higher inside the cell than outside, so opening of non-specific cation channels would cause potassium outflux. But
along with sodium and calcium influx, the net effect is depolarization.
endotropic: "their data argues that NMDA voltage dependence is independent of magnesium."
>> Voltage dependant block of NMDARs by Mg is still very much a factor. This paper simply describes an additional voltage dependant conformational change in subunit
NR2B which contributes to channel opening. This is relevent only to NMDA receptors that incorporate NR2B. NR1/2A for example would not see this effect.
