GLUTAMATE RECEPTOR IN HEALTH & DISEASES

DR SHASHIKANT BHARGAVA

Glutamate

Glutamate receptor

General clinical implications

Associated conditions

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

Glutamate: biochemistry

Glutamate: physiology

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.

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

Ionotropic receptor- features

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.

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.

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.

EXCITOTOXICITY

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"

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.

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.

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.

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

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.

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.

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

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

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.

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

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

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

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

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

Schizophrenia◦ Glycine agonist: D-serine, D-alanine, D-cycloserine, Sarcosine (GlyT1 inhibitor)

CX516, Farampator: AMPA modulator: improves memory

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

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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