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The fact that there are several binding sites for many different molecules on
the NMDA receptor highlights the interconnected modulation achieved through a
combination of all the chemicals. As well as the glutamate and glycine binding
site, there is a polyamine regulatory site, which facilitates opening of the channel
upon activation by the appropriate molecules such as spermine and spermidine.
The drugs ifenprodil and eliprodil are often administered to protect against neural
damage after ischaemia and trauma and they act as antagonists to
this binding site suggesting polyamines may have a role in the mediation of
excitotoxicity. Then there are two inhibitory sites, one being a voltage-dependent
Mg2+ site, and the other a Zn2+ voltage-independent site at the mouth of the
channel. The last binding site is known as the PCP site because of the high affinity
to the drug phencyclidine however it does bind other noncompetitive antagonists
such as ketamine. The discovery of this site has led to the belief that glutamate
transmission is associated with schizophrenia since individuals, who
recreationally use PCP, often exhibit signs similar to those suffering from
schizophrenia.
The receptors AMPA and kainate are often separated into a class known as
the non-NMDA receptors because of their structural similarities to each other. In
contrast to the slow excitatory potential instigated by the NMDA receptors, these
receptors mediate rapid excitatory synaptic transmission and thus if they are
blocked, brain function shows down completely. While AMPA receptors are
found widely distributed throughout the neural pathways, kainate receptors have a
limited distribution being found primarily in the stratum lucidum region of the
hippocampus. They consist of a tetramer structure, the AMPA receptor
comprising GluR 1-4 subunits and the kainate receptor GluR 5-7 subunits as well
as KA 1,2 subunits. Depending on the subunit structure, a given non-NMDA
receptor will display different characteristics, for example higher permeability can
be granted to AMPA receptors if they lack the GluR2 subunit. Kainate receptors
are also thought to extend a degree of presynaptic inhibition.
The metabotropic dimeric receptor is the last type of glutamate receptor and
is either linked to a Gq or Gi protein when glutamate binds to its specific site on
the N-terminal tail. They exist both at the pre-synaptic and post-synaptic regions
throughout the nervous system as well as on the membranes of the glial cells.
They act mainly though inhibiting K+ channels or Ca2+ channels thus exerting a
postsynaptic excitatory effect. They can be activated by glutamate, trans -APCD,
quisqualate and ibotenate and they can be antagoinsed by pertussis toxin. Eight
different subtypes of the metabotropic receptor have now been identified, the first
subgroup comprising mGluR1 and mGluR5 being coupled to PIP2 and the second
subgroup of mGluR2 – mGluR4 and mGluR5 - mGluR 8 being negatively
coupled to adenylate cyclase. The receptors are believed to play a role both in
synaptic modulation and excitotoxicity however because of the dearth of suitable
agonists and antagonists, not much is known specifically about their functions.
Two major physiological process, which the NMDA and metabotropic
glutamate receptors contribute significantly to, are the concepts of excitotoxicity
and synaptic plasticity. Since glutamate is a neurotransmitter, one would not
expect that it would act as a toxin to neurons but surprisingly in the 1970s when
glutamate was given orally, there was significant neurodegeneration. Initially this
was extremely worrying because of the chemical's common use as a food additive,
MSG. Indeed several consumers would experience the so-called Chinese
restaurant syndrome, suffering from neck stiffness, chest pain and even
tachycardia. This is an example of excitotoxicity, which essentially results from
the release of glutamate on neurons leading to cell death. Glutmate binds to the
metabotropic, NMDA and AMPA receptor. Activation of the AMPA receptor
leads to depolarisation resulting in opening of the NMDA channels allowing an
influx of Ca2+. The action potential will also open voltage-gated Ca2+ channels
causing
further Ca2+ influx. The metabotropic receptors will react through the IP3 second
messenger thus mobilising intracellular stores of Ca2+ from the endoplasmic
reticulum. Channels, which also allow in Na+, will further contribute to Ca2+
influx though promotion of the Ca2+/Na+ exchange. Additionally, the
depolarisation instigated will also inhibit the uptake of the glutamate reinforcing
the impact of the extracellular glutamate concentration. The dramatic elevation in
intracellular Ca2+ concentration is a well-known signal for cellular apoptosis. It
activates calpains, lipases, NO synthases, which can cause damage through the
free radicals and perioxynitrie, and increases arachidonic acid encouraging more
free radical production and inhibiting glutamate uptake release and glutamate
release. However there are a number of mechanisms designed to maintain a
comfortable concentration of Ca2+. These include the Ca2+ efflux pump, Na+
pump and the mitochondria and endoplasmic reticulum in their ability to act as a
sink for Ca2+. When Ca2+ rises dramatically though, a positive feedback system
is reached often leading to cell death. Mitochondrial stores of calcium can exceed
beyond the capacity of the organelle hence disrupting the activity of the
mitochondria and reducing ATP synthesis. This notion of hindered mitochondrial
function exposing neurons to exocitotoxicity is believed to be a factor in
Parkinson's disease. History has demonstrated the dire consequences of
excitotoxicity. β-methylamino-alanine, an amino acid found in the seeds of a
plant indigenous to Guam, caused dementia, paralysis and Parkinson's disease
through this mechanism.
In 1949 the Canadian psychologist Donald Hebb, proposed a theory saying
that the repeated firing of one axon onto another induces structural and metabolic
changes, which increase the efficiency of the neural impulse i.e. “inputs that fire
together, wire together”. Hebbian theory formed the foundation of the idea of
synaptic plasticity. Synaptic plasticity involves the changes to a neuron, which
alter synaptic connectivity and efficacy. It can result from physiological variations
such as in learning or pathological methods such as in epilepsy, the main ones of
which are known as long-term potentiation (LTP) and long-term depression
(LTD) and involve glutamate receptors. LTP occurs in neurons nearly
everywhere, improving the efficiency of synaptic transmission and lasting weeks
in vivo. It results from the terse burst of high frequency pre-synaptic stimulation
while LTD is caused by longer periods of lower frequency stimuli. In order for
LTP to occur, both pre-synaptic and postsynaptic neurons must be simultaneously
active and this is believed to be the basis of memory. Activation of both neurons
means activation of AMPA receptors. Also the response of AMPA receptors in
the postsynaptic neuron is increased, expression and trafficking of AMPA
receptors to the appropriate sites is increased, and it is believed glutamate release
is elevated. Evidence also shows that activation of the NMDA and metabotropic
receptors sensitises the AMPA receptors encouraging a greater response form
them when stimulated.
In CA1 cells in the Ammon's horn of the hippocampus, the intracellular rise
in Ca2+ induced by the NMDA receptor activation is thought to be directly linked
to LTP and this notion has been reinforced by illustrating inhibition of LTP after
administration of Ca2+ chelator. Elevation of Ca2+ activates Protein Kinase C
and calcium-calmodulin-dependent protein kinase II. The cascade beyond this
process still remains very much in the dark. Some believe that phosphorylation
increases the effectiveness of postsynaptic AMPA receptors through one of the
kinases, others say it leads to insertion of new AMPA receptors in the membrane.
Some evidence shows that vesicles of AMPA receptors fuses with the
postsynaptic membrane upon CaMKII activation. It has also been noted that
structural changes can be observed after LTP. Synapses seem to sprout and
postsynaptic dendrite spines appear to bud forming new synaptic contacts with
additional axons. This combination of rearrangement increases the responsive
postsynaptic surface as well as the probability that a given action potential will
trigger release of glutamate.
Understanding the glutamate receptors and their neuronal effects is essential
to the understanding of several significant biochemical processes and substantial
pathologies. They are thought to have a role in schizophrenia, bipolar disorder,
Alzheimer's and Parkinson's and their manipulation has given rise to some key
drugs with unparalleled usefulness. However much of glutamate's roles in the
body still remain elusive especially the idea of synaptic plasticity. Only further
research can expose the mechanisms of such an intricate process and allow for the
discovery of more useful compounds and forms of treatment.