Glutamate receptors Flashcards
Metabotropic glutamate receptors Group I
- mGluR1, mGluR5
- Gq → PLC, Ca2+
Metabotropic glutamate receptors Group II
mGluR2, mGluR3
* Gi → ↓ cAMP
Metabotropic glutamate receptors Group III
mGluR4, mGluR6, mGluR7, mGluR8
* Gi → ↓ cAMP
Group I mGluR found mostly
postsynaptically
Group II and III are often found
presynaptically
Group II and III are often found presynaptically
Autoreceptors
* Modulators on other NT systems
Metabotropic glutamate receptors Contribute to
plasticity of synapses
Metabotropic glutamate receptors Excitatory or inhibitory depending on
signalling, cell types
Knockout studies mGluR1 KO show
motor dysfunction
mGluR1 KO show motor dysfunction
Ataxia, intention tremor, dysmetria
* Impaired plasticity in the cerebellum
- mGluR2 KO show
normal synaptic
transmission
mGluR2 KO show normal synaptic
transmission
Highly expressed in dentate gyrus
* KO shows reduced presynaptic inhibition
Receptor
distribution At postsynaptic densities mGluR
are expressed at the
periphery.
Receptor
distribution AMPAR and NMDAR are
distributed
throughout the PSD
Receptor
distribution NMDAR are
tightly coupled to
Ca2+
-dependent proteins such as
CaMKII
Plasticity Hippocampus
- Important for learning and
memory
Plasticity Synaptic plasticity
Changes in strength of
glutamatergic synapses in
response to activity
Plasticity LTP
persistent increase in synaptic
strength following tetanic
activity (100 Hz, 1 s)
Plasticity * Long-term depression (LTD)
persistent decrease in
synaptic strength following
slow repetitive activity
Plasticity in the HC
Hippocampal plasticity is widely
studied due to the role in learning
and the well defined circuits (most
glutamatergic).
LTP occurs through
coincidence detection
CaMKII is coupled to
NMDAR
Ca2+-calmodulin dependent
protein kinase II (CamKII) Localizes with NMDA receptors
(intracellular face)
Phosphorylates numerous
cellular targets and initiates
early-phase of LTP
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
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
