Topic 11: Glutamate Receptors Flashcards
What are group 1 metabotropic glutamate receptors?
mGluR1, mGluR5
Gq –> PLC, calcium
What are group 2 metabotropic glutamate receptors?
mGluR2, mGluR3
Gi –> decreased cAMP
What are group 3 metabotropic glutamate receptors?
mGluR4, mGluR6, mGluR7, mGluR8
Gi –> decreased cAMP
What are the characteristics of metabotropic glutamate receptors?
group 1 mGluR found mostly post-synoptically
group 2 and 3 are often found pre-synoptically: autoreceptors, modulators on other NT systems
contribute to plasticity of synapses
excitatory or inhibitory depending on siganalling, cell types
What are the results of mGluR1 knockout studies?
show motor dysfunction
ataxia, intention tremor, dysmetria
impaired plasticity in the cerebellum
What are the results of mGluR2 knockout studies?
show normal synaptic transmission
highly expressed in dentate gyrus
KO shows reduced presynaptic inhibition
What are the results of mGluR4 knockout studies?
show loss of synaptic efficiency during repetitive activation
presynaptic regulation in cerebellum
maintenance of normal motor function
What is glutamate receptor distribution?
at postsynaptic densities mGluR are expressed at the periphery
AMPAR and NMDAR are distributed throughout the PSD
NMDAR are tightly coupled to calcium-dependent proteins such as CaMKII (Calmodulin-dependent kinase II)
What is synaptic plasiticity?
changes in strength of glutamatergic synapses in response to activity
What is long-term potentiation (LTP)?
persistent increase in synaptic strength following tetanic activity
100 Hz, 1 second
What is long term depression (LTD)?
persistent decrease in synaptic strength following slow repetitive activity
1 Hz, 10 minutes
What is plasticity in the hippocampus?
hippocampal plasticity is widely studied due to the role in learning and the well defined circuits (most glutamatergic)
hippocampal slice preparations (ex vivo preparation) leave the PP –> DG –> CA3 –> CA1 circuit intact and accessible
What is CaMKII?
CaMKII is coupled to NMDAR
calcium-calmodulin dependent protein kinase II (CaMKII)
localizes with NMDA receptors (intracellular face)
phosphorylates numerous cellular targets and initiates early-phase of LTP
What is early long term potentiation?
calcium-entry through NMDAR activates CamKII
CamKII phosphorylates AMPAR - increasing their sensitivity to glutamate
signaling 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
What is late-phase long term potentiation?
activation of CamKII and PLC converge on another signaling kinase, ERK (extracellular-signal regulated kinase)
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
How are the NMDA receptors involved in long term potentiation?
LTP induction depends critically on NDMAR
NMDAR overexpression increases learning in mice
mice engineered to overexpress the NR2B subunit
increased retention in novel object recognition tasks
What is the excitotoxicity of glutamate?
glutamate and excitatory analogues can be neurotoxic
MSG can induce lesions
occurs through over activation of glutamatergic neurons
increased intracellular calcium to dangerous levels
contributes to pathogenesis of ischemia, ALS, traumatic brain injury, alcoholism, Huntington’s disease, multiple sclerosis
What is Lytigo-bodig disease?
a neurodegenerative disease that manifests similar to ALS and Parkinson’s
localized in Guam
local cycad seeds contain beta-methyl-amino-L-alanine (BMAA)
seeds eaten by fruit bats, accumulates in fat stores, fruit bats eaten by locals
BMAA potent excitotoxin at AMPA, kainate, and NMDA receptors
How does EAAT2 dysfunction lead to excitotoxicity?
a mutation found in ALS patients leads to increased intracellular calcium 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
How does ischemia lead to excitotoxicity?
ischemic stroke results in loss of blood flow to regions of the CNS
lack of oxygen and glucose causes energy failure: energy-dependent processes fail (e.g., Na+/K+ ATPase)
loss of ionic gradients causes glutamatergic synapses to dump glutamate: increased intracellular Ca2+ (exocytosis), failure of EAAT transport (depends on ion gradient) reverses glutamate flow
What is necrosis?
uncontrolled cell death
Na+ and Cl- influx to cell causes hypertonicity
osmosis causes cell swelling (edema)
swelling leads to rupture of the cell membrane and cell lysis
What is apoptosis?
programmed cell death
calcium influx activities 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
What is cell death?
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
What is glutamatergic cell death?
NMDA and AMPA receptors are interesting targets for neuroprotective agents in ischemia
in animal models, NMDA or AMPA antagonists reduce the volume of injury in ischemic stroke: translation to humans is difficult, timing of intervention is challenging, clinical trials for stroke are very difficult due to the acute nature of injury
