Glutamate receptors Flashcards by Cambell Meier

Metabotropic glutamate receptors Group I

mGluR1, mGluR5
Gq → PLC, Ca2+

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Metabotropic glutamate receptors Group II

mGluR2, mGluR3
* Gi → ↓ cAMP

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Metabotropic glutamate receptors Group III

mGluR4, mGluR6, mGluR7, mGluR8
* Gi → ↓ cAMP

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Group I mGluR found mostly

postsynaptically

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Group II and III are often found

presynaptically

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Group II and III are often found presynaptically

Autoreceptors
* Modulators on other NT systems

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Metabotropic glutamate receptors Contribute to

plasticity of synapses

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Metabotropic glutamate receptors Excitatory or inhibitory depending on

signalling, cell types

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Knockout studies mGluR1 KO show

motor dysfunction

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mGluR1 KO show motor dysfunction

Ataxia, intention tremor, dysmetria
* Impaired plasticity in the cerebellum

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mGluR2 KO show

normal synaptic
transmission

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mGluR2 KO show normal synaptic
transmission

Highly expressed in dentate gyrus
* KO shows reduced presynaptic inhibition

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Receptor
distribution At postsynaptic densities mGluR
are expressed at the

periphery.

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Receptor
distribution AMPAR and NMDAR are
distributed

throughout the PSD

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Receptor
distribution NMDAR are

tightly coupled to
Ca2+
-dependent proteins such as
CaMKII

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Plasticity Hippocampus

Important for learning and
memory

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Plasticity Synaptic plasticity

Changes in strength of
glutamatergic synapses in
response to activity

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Plasticity LTP

persistent increase in synaptic
strength following tetanic
activity (100 Hz, 1 s)

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Plasticity * Long-term depression (LTD)

persistent decrease in
synaptic strength following
slow repetitive activity

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Plasticity in the HC

Hippocampal plasticity is widely
studied due to the role in learning
and the well defined circuits (most
glutamatergic).

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LTP occurs through

coincidence detection

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CaMKII is coupled to

NMDAR

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Ca2+-calmodulin dependent
protein kinase II (CamKII) Localizes with NMDA receptors
(intracellular face)

Phosphorylates numerous
cellular targets and initiates
early-phase of LTP

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LTP and glutamate

repeated stimulation very quickly - repeated activation of AMPA receptors causes depolarization across membrane - allows MG to be removed from NMDA receptor - calium flows in - result is LTP

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early-phase of LTP Ca2+

entry through NMDAR activates CamKII

Early LTP CamKII

phorphorylates AMPAR – increasing their sensitivity to glutamate

Early LTP CamKII phorphorylates AMPAR – increasing their sensitivity to glutamate. Signalling cascades

increase trafficking of AMPAR to the postsynaptic density – increasing the availability of receptors.

Early LTP Ca2+ -entry through NMDAR activates CamKII . CamKII phorphorylates AMPAR – increasing their sensitivity to glutamate. Signalling cascades increase trafficking of AMPAR to the postsynaptic density – increasing the availability of receptors. Retrograde messengers

signal to the presynaptic cell initiating presynaptic changes that increase glutamate release.

Late-phase LTP Activation of CamKII and PLC converge on another signalling kinase

ERK

Late-phase LTP ERK triggers downstream changes including phosphorylation of transcription factors

Gene synthesis is induced increasing production of AMPA receptors

Synthesis processes are important for

long-term maintenance of potentiation

NMDA receptors and LTP NMDAR overexpression increases

learning in mice

Mice engineered to overexpress the NR2B subunit * Termed Doogie mouse… * Increased

retention in novel object recognition tasks

Excitotoxicity Glutamate and excitatory analogues can be

neurotoxic specifically when extracellularly

MSG can induce

lesions

lesions can be induces by other

agonists of the glutamate receptor

Excitotoxicity Occurs through

over activation of glutamatergic neurons

Excitotoxicity Increased intracellular

Ca2+ to dangerous levels

Increased intracellular Ca2+ to dangerous levels Contributes to (6)

pathogenesis of ischemia, ALS, traumatic brain injury, alcoholism, Huntington’s disease, multiple sclerosis

Lytigo-bodig disease is a

neurodegenerative disease that manifests similar to ALS and Parkinson’s

Lytigo-bodig disease is Localized in

Guam

Local cycad seeds (Cyas circinalis) contain

BMAA

BMAA potent

excitotoxin at AMPA, kainate, and NMDA receptors

* A mutation found in ALS patients leads to increased

intracellular Ca2+ in motor neurons, which stresses mitochondria. Mitochondria produce reactive oxygen species (ROS) that are toxic and also inhibit EAAT2 on astrocytes

EAAT2 dysfunction leads to

glutamate accumulation and excitotoxicity in motor neurons.

Ischemia

* Ischemic stroke results in loss of blood flow to regions of the CNS

Ischemia Lack of O2 and glucose causes

energy failure

Ischemia Loss of ionic gradients causes

glutamatergic synapses to dump glutamate

Loss of ionic gradients causes glutamatergic synapses to dump glutamate

ncreased intracellular Ca2+ Failure of EAAT transport (depends on ion gradient) reverses glutamate flow

Excitotoxic cell death Necrosis

Uncontrolled cell death

Necrosis process

* Na+ and Cl influx to cell causes hypertonicity -Osmosis causes cell swelling (edema) -Swelling leads to rupture of the cell membrane and cell lysis

Excitotoxic cell death Apoptosis

Programmed cell death

Apoptosis Process

Ca2+ influx activates intracellular pathways - Mitochondrial generation of ROS • Depolarization and swelling of mitochondria Mitochondrial damage leads to formation of pores in mitochondrial membrane • Cytochrome C escapes • Initiates apoptosis

Two modes of cell death are initiated

by ischemic / glutamatergic injury

Apoptosis is regulated cell death and results in

controlled removal of cell material by phagocytic cells.

Necrosis results in cell lysis and

release of cellular contents.

Glutamatergic cell death In animal models, NMDA or AMPA antagonists reduce the volume of injury in

n ischemic stroke

Glutamatergic cell death - Glutamate can cause

over-excitation leading to cell death by necrosis or apoptosis → Excitotoxicity

Epileptiform activity Epilepsy

Heterogeneous group of neurological disorders characterized by epileptic seizures

* Epilepsy Abnormal

excessive or synchronous neuronal activity in the brain

Epilepsy and glutamatergic activity

Epileptic seizures are dependent on glutamatergic signalling

* Pharmacological activation of glutamatergic signalling can initiate

seizures in animal models

convulsant

Kainate, AMPA, domoic acid are convulsants

Early seizure activity is dependent on

AMPA receptor activation

Antagonists of AMPAR can

prevent seizure onset (e.g. NBQX

As seizures intensify and spread

NMDA receptors are involved

Antagonists of NMDAR can reduce

Intensity and duration of seizures (e.g. MK801)

Genetic causes of epilepsy * Glutamatergic changes are found in many heritable cases of epilepsy -

Heterogeneous

Genetic causes of epilepsy - Glutamate receptors

AMPA, kainate, and NMDA receptor subunits altered

Genetic causes of epilepsy -Glutamate transporters

* EAAT 1 and 2 show alterations in patients

Genetic causes of epilepsy - Astrocytic glutamate recycling

Glutamine synthetase, glutamate dehydrogenase

Epilepsy treatment (AEDs)

Anticonvulsants/antiepileptic drugs (AEDs) are one of the few drug classes that is not tested against placebo

AEDs typically target

et Na+ channel activity or increase inhibitory signalling by affecting GABA

* 30% of patients are unresponsive to

AED therapy

AEDs often lose

effectiveness over time

Surgical resection of seizure focus remains a

common treatment of drug-resistant epilepsy

Corpus callostomy

Corpus callostomy is effective at decreasing the frequency and amplitude of seizures by disrupting bilateral synchronous discharges.

Corpus callostomy Side effects

s include speech irregularities – inability to engage in spontaneous speech, inability to follow verbal commands using non-dominant hand, and alien hand syndrome