Glutamate receptor
Glutamate is also used by the brain to synthesize GABA (γ-Aminobutyric acid), the main inhibitory neurotransmitter of the mammalian central nervous system.
One of the major functions of glutamate receptors appears to be the modulation of synaptic plasticity, a property of the brain thought to be vital for memory and learning.
[7][8][9] Additionally, metabotropic glutamate receptors may modulate synaptic plasticity by regulating postsynaptic protein synthesis through second messenger systems.
They are unique in that they require both glutamate and the co-agonist glycine to activate, and they are also voltage-dependent, meaning they only open when the postsynaptic membrane is depolarized.
NMDA receptors are permeable to calcium ions, which can trigger intracellular signaling pathways that lead to changes in synaptic strength.
Each subtype of glutamate receptor has a unique function and plays a crucial role in neuronal communication and plasticity.
[11] Furthermore, brain slices show glutamate receptors are ubiquitously expressed in both developing and mature astrocytes and oligodendrocytes in vivo.
NMDA receptors have an internal binding site for an Mg2+ ion, creating a voltage-dependent block, which is removed by outward flow of positive current.
[28] Numerous ionotropic glutamate receptor subunits are expressed by heart tissue, but their specific function is still unknown.
[30] AMPA iGluRs modulate the secretion of insulin and glucagon in the pancreas, opening the possibility of treatment of diabetes via glutamate receptor antagonists.
Various neurological disorders are accompanied by antibody or autoantigen activity associated with glutamate receptors or their subunit genes (e.g. GluR3 in Rasmussen's encephalitis,[34] and GluR2 in nonfamilial olivopontocerebellar degeneration).
[39] Ingestion of or exposure to excitotoxins that act on glutamate receptors can induce excitotoxicity and cause toxic effects on the central nervous system.
Excessive extracellular glutamate concentrations reverse xCT, so glial cells no longer have enough cystine to synthesize glutathione (GSH), an antioxidant.
[41] Lack of GSH leads to more reactive oxygen species (ROSs) that damage and kill the glial cell, which then cannot reuptake and process extracellular glutamate.
High NO concentration damages mitochondria, leading to more energy depletion, and adds oxidative stress to the neuron as NO is a ROS.
Conditions such as exposure to excitotoxins, old age, congenital predisposition, and brain trauma can trigger glutamate receptor activation and ensuing excitotoxic neurodegeneration.
Administered NMDA antagonists in a clinical setting produce significant side effects, although more research is being done in intrathecal administration.
[50] A SciBX article in January 2012 commented that "UPenn and MIT teams have independently converged on mGluRs as players in ADHD and autism.
In small studies, memantine has been shown to significantly improve language function and social behavior in children with autism.
Diabetes mellitus, an endocrine disorder, induces cognitive impairment and defects of long-term potential in the hippocampus, interfering with synaptic plasticity.
[40] Using folic acid has been proposed as a possible treatment for Huntington's due to the inhibition it exhibits on homocysteine, which increases vulnerability of nerve cells to glutamate.
[64] Antagonists for NMDA and AMPA receptors seem to have a large benefit, with more aid the sooner it is administered after onset of the neural ischemia.
[65] Inducing experimental autoimmune encephalomyelitis in animals as a model for multiple sclerosis(MS) has targeted some glutamate receptors as a pathway for potential therapeutic applications.
[66] This research has found that a group of drugs interact with the NMDA, AMPA, and kainate glutamate receptor to control neurovascular permeability, inflammatory mediator synthesis, and resident glial cell functions including CNS myelination.
[40] In vitro spinal cord cultures with glutamate transport inhibitors led to degeneration of motor neurons, which was counteracted by some AMPA receptor antagonists such as GYKI 52466.
[36] In schizophrenia, the expression of the mRNA for the NR2A subunit of the NMDA glutamate receptor was found to be decreased in a subset of inhibitory interneurons in the cerebral cortex.
Refractory schizophrenia patients showed associated improvements in both negative and positive symptoms, underscoring the potential uses of GluR antagonists as antipsychotics.
Scientists have proposed that specific antagonists can act on GABAergic interneurons, enhancing cortical inhibition and preventing excessive glutamatergic transmission associated with schizophrenia.
Using rodent models, labs have found that the introduction of antagonists to these glutamate receptors helps counteract the epileptic symptoms.
[73] Since glutamate is a ligand for ligand-gated ion channels, the binding of this neurotransmitter will open gates and increase sodium and calcium conductance.
