role of glutamate receptoe in health and diseases

1. GLUTAMATE RECEPTOR
IN HEALTH & DISEASES
DR SHASHIKANT BHARGAVA

2. Glutamate
Glutamate receptor
General clinical implications
Associated conditions

3. Glutamate
Glutamate: found in very high concentrations in brain; have powerful excitatory effects on
neurons in virtually every region of the CNS
Glutamate in the CNS comes mainly from either glucose, via the Krebs cycle, or glutamine, which
is synthesized by glial cells and taken up by the neurons
The interconnection between the pathways for the synthesis of EAAs and inhibitory amino acids
(GABA and glycine), makes it difficult to use experimental manipulations of transmitter synthesis
to study the functional role of individual amino acids
The action of glutamate is terminated mainly by carrier-mediated reuptake into the nerve
terminals and neighbouring astrocytes

4. Glutamate: biochemistry

5. Glutamate: physiology

6. Glutamate receptors
Glutamate and related excitatory amino acids activate both ionotropic (ligand-gated cation
channels) and metabotropic (G-protein-coupled) receptors
Ionotropic glutamate receptors (iGluRs) form the ion channel pore that activates when
glutamate binds to the receptor.
Metabotropic glutamate receptors (mGluRs) indirectly activate ion channels on the plasma
membrane through a signaling cascade that involves G proteins. Ionotropic glutamate receptors
are most abundant in the cortex, basal ganglia and sensory pathways. NMDA and AMPA
receptors are generally co-localised, but kainate receptors have a much more restricted
distribution.

8. Ligand-gated channels can be homomeric or heteromeric assemblies of four subunits, each with
the 'pore loop' structure
Receptors comprising different subunits can have different pharmacological and physiological
characteristics, e.g. AMPA receptors lacking the GluA2 subunit have much higher permeability to
Ca2+ than the others, which has important functional consequences; mGLUR5 associated with
cocaine self-administration and craving

9. Ionotropic receptor- features

10. NMDA receptor
Highly permeable to Ca2+, as well as to other cations, so activation of NMDA
receptors is particularly effective in promoting Ca2+ entry.
Readily blocked by Mg2+, and this block shows marked voltage dependence. Occurs
at physiological Mg2+ concentrations when the cell is normally polarised, but
disappears if the cell is depolarised.
Activation of NMDA receptors requires glycine as well as glutamate. The binding site
for glycine is distinct from the glutamate binding site, and both have to be occupied
for the channel to open. Competitive antagonists at the glycine site indirectly inhibit
the action of glutamate.

12. Synaptic plasticity & LTP
AMPA and kainate receptors mediate fast depolarization. NMDA receptors are involved in
normal synaptic transmission, but activation of NMDA receptors is usually associated more
closely with the induction of various forms of synaptic plasticity rather than with fast point-to-
point signaling in the brain
Synaptic plasticity is a general term used to describe long-term changes in synaptic connectivity
and efficacy, either following physiological alterations in neuronal activity (as in learning and
memory), or resulting from pathological disturbances (as in epilepsy, chronic pain or drug
dependence).
Synaptic plasticity underlies much of what we call 'brain function‘; no single mechanism is
responsible; however, one significant and much-studied component is long-term potentiation
(LTP), a phenomenon in which AMPA and NMDA receptors play a central role.

14. Excitotoxicity
High concentrations of glutamate lead to neuronal cell death by mechanisms that have only
recently begun to be clarified.
The cascade of events leading to neuronal death is thought to be triggered by excessive
activation of NMDA or AMPA/kinase receptors, allowing significant influx of Ca2+ into neurons.
Glutamate-mediated excitotoxicity may underlie the damage that occurs after ischemia or
hypoglycemia in the brain, during which a massive release and impaired reuptake of glutamate
in the synapse leads to excess stimulation of glutamate receptors and subsequent cell death.

15. EXCITOTOXICITY

16. Disease associations with Glutamate
Attention deficit hyperactivity disorder (ADHD)
Glutamate receptor subunit gene GRIN2B (responsible for key functions
in memory and learning) and SLC1A3 solute carrier gene-encoding part of the glutamate
transporter found associated with ADHD.
In 1 study it was concluded that "CNVs affecting metabotropic glutamate receptor genes
were enriched across all cohorts", "over 200 genes interacting with glutamate receptors [. .] were
collectively affected by CNVs", "major hubs of the (affected genes') network
include TNIK50, GNAQ51, and CALM", and "the fact that children with ADHD are more likely to
have alterations in these genes reinforces previous evidence that the GRM pathway is important
in ADHD"

17. Autism
The etiology of autism may include excessive glutaminergic mechanisms. In small
studies, memantine has been shown to significantly improve language function and social
behavior in children with autism
A link between glutamate receptors and autism was also identified via the structural
protein ProSAP1 SHANK2 and potentially ProSAP2 SHANK3. The study authors concluded that the
study "illustrates the significant role glutamatergic systems play in autism" and "By comparing
the data on ProSAP1/Shank2−/−mutants with ProSAP2/Shank3αβ−/− mice, we show that different
abnormalities in synaptic glutamate receptor expression can cause alterations in social
interactions and communication.

18. Ischemia
This is linked to an inadequate supply of ATP, which drives the glutamate transport levels that
keep the concentrations of glutamate in balance. This usually leads to
excitotoxicity. Antagonists for NMDA and AMPA receptors seem to have a large (time-depandant)
benefit
Aching
Hyperalgesia is directly involved with spinal NMDA receptors. Since spinal NMDA receptors link
the area of pain to the brain's pain processing center, the thalamus, these glutamate receptors
are a prime target for treatment.

19. Huntington's disease
A specific genotype of human GluR6 was discovered to have a slight influence on the age of onset
of Huntington's disease
Also proposed to exhibit metabolic and mitochondrial deficiency, which exposes striatal neurons
to the over activation of NMDA receptors. 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.

20. Diabetes mellitus
Induces cognitive impairment and defects of long-term potential in the hippocampus,
interfering with synaptic plasticity. (Malfunctioning NMDA glutamate receptors in the
hippocampus during early stages of the disease)
Research being using hyperglycemia and insulin to regulate these receptors and restore cognitive
functions.
Pancreatic islets regulating insulin and glucagon levels also express glutamate receptors

21. Multiple sclerosis
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. Oligodendrocytes in the CNS myelinate axons; the
myelination dysfunction in MS is partly due to the excitotoxicity of those cells.
The experiments showed improved oligodendrocyte survival, and remyelination increased.
Furthermore, CNS inflammation, apoptosis, and axonal damage were reduced.

22. Parkinson's disease
Late onset symptoms may be partially due to glutamate binding NMDA and AMPA glutamate
receptors.
In vitrospinal cord cultures with glutamate transport inhibitors led to degeneration of motor
neurons, which was counteracted by some AMPA receptor antagonists such as GYKI 52466.
Research also suggests that the metabotropic glutamate receptor mGlu4 is directly involved in
movement disorders associated with the basal ganglia through selectively modulating glutamate
in the striatum.

23. Schizophrenia
In schizophrenia, the expression of the NR2A subunit of NDMA receptors in mRNA was
experimentally undetectable in 49-73% in GABA neurons that usually express it.
These are mainly in GABA cells expressing the calcium-buffering
protein parvalbumin (PV), which exhibits fast-spiking firing properties and target the pyramidal
neurons. The study found the density of NR2A mRNA-expressing PV neurons was decreased by as
much as 50% in subjects with schizophrenia.
Observations suggest glutamatergic innervation of PV-containing inhibitory neurons
appears to be deficient in schizophrenia

24. The expression of the mRNA for the GluR5 kainate receptor in GABA neurons has also
been found to be changed in patients with schizophrenia
Paradoxically, Memantine- a weak, nonselective NMDA receptor antagonist, was used as
an add-on to clozapine therapy in a clinical trial. Refractory schizophrenia patients showed
associated improvements in both negative and positive symptoms, underscoring the potential
uses of GluR antagonists as antipsychotics

25. Seizures
Glutamate receptors have been discovered to have a role in the onset of epilepsy. In rodent
models, it was found that the introduction of antagonists to these glutamate receptors helps
counteract the epileptic symptoms. Group 1 metabotropic glutamate receptors (mGlu1 and
mGlu5) are the primary cause of seizing, so applying an antagonist to these receptors helps in
preventing convulsions.

26. Autoimmunity associated with Glutamate receptor
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, and
GluR2 in nonfamilial olivopontocerebellar degeneration

27. Neurodegenerative diseases suspected to have a link mediated through stimulation of glutamate
receptors:
AIDS dementia complex
Alzheimer's disease
Amyotrophic lateral sclerosis
Depression/anxiety
Drug addiction, tolerance, and dependency
Glaucoma
Hepatic encephalopathy
Neuropathic pain syndromes

29. Competitive NMDA antagonist: AP-5, CPP
Non-Competitive NMDA antagonist/channel blocker: ketamine, phencyclidine, dizocilpine
Glycine site agonist: Glycine, D-serine
Glycine site antagonist: 7-chloro-kynurenic acid
Polyamine site agonist: spermine
Polyamine site antagonist: ifenprodil, eliprodil
AMPA & Kainate antagonist: NBQX

30. Analgesic: Tezampanel (migraine, dental pain): GluK1 inhibitor: PC
ALS: Talampanel: AMPA blocker; II
Neuropathic pain
◦ palampanel: AMPA blocker; II
◦ GluN2b blockers
Refractory partial seizure
◦ Talampanel: AMPA blocker; II
Stroke prevention
◦ Aptigenal: channel blocker; fIII
◦ Gavestinel: glycine antagonist; f
◦ NBQX & analogues (ZK200775 and YM872): kainate blocker

31. Depression
◦ CP-101,606: GluN2b blocker
Neurodegeneration
◦ Amantadine:weak NMDA antagonist
◦ Remacenide: NMDA channel blocker
◦ MK0657 and radiprodil: GluN2b antagonist
◦ Memantine: NMDA channel blocker
◦ Approved for mild to moderate Alzheimer’s disease
◦ Vascular dementia, Parkinsonism

32. Schizophrenia
◦ Glycine agonist: D-serine, D-alanine, D-cycloserine, Sarcosine (GlyT1 inhibitor)
CX516, Farampator: AMPA modulator: improves memory

33. Approved drugs acting via Glutamate receptor
Memantine: Alzheimer’s disease
Ketamine: General Anaesthetic
Acamprosate: alcohol deaddiction
Felbamate: seizure disorder
Riluzole: (decrease Glu release);ALS, Huntington’s disease
Topiramate: (kainate blocker); seizure disorder, migraine

34. References
Rang & Dale’s Pharmacology; 7th edition; chapter 37
Goodman & Gilman’s the pharmacological basis of therapeutics;12th ed; chapter 14
Stephan Treynelis et al; Glutamate receptor ion channel- structure, regulation and function; Phar
Review 2010; 405-96
Petroff OA (December 2002). "GABA and glutamate in the human brain". Neuroscientist 8 (6):
562–573.
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