Wednesday, 3-23-NT Excitotoxicity (Karius) Flashcards
___ is an EAA dervied from OAA, documented as a NT in the visual cortex and pyramidal cells
Aspartate—> often found with glutamate
What type of receptor(s) can be activated by EAA’s?
Both ionotropic and metabotropic
___ is an ionotropic receptor for EAA’s that are activated by exogenous N-methyl-D-aspartate as well as by glutamate and aspartate. When it is activated, it allows Ca influx and has multiple modulatory sites, including a Glycine binding site, PCP binding site, and a Mg binding site
NMDA receptor
Describe the role of Glycine when it binds to the NMDA receptor?
Glycine serves as a CO-AGONIST
- Presence of glycine is required for the EAA to have effect
- Glycine on its own CANNOT open the channel
Where is the Mg binding site on the NMDA receptor?
Inside the channel.
-Mg blocks the channel –> channel must open and cell must be depolarized for Mg to leave
Where is the PCP binding site on the NMDA receptor?
Inside the channel (internal to Mg2+ site)
-Blocks the channel
Activation of the NMDA receptor leads to ___
EPSP in the post-synaptic cell–> Slow onset (Time to remove Mg), prolonged duration (Ca slower)
What are the 2 subtypes (pharmacological) of the Non-NMDA receptors?
AMPA
Kainate
In order to get rid of EAA’s, ___ utilize uptake systems that are of high affinity and are Na+ dependent secondary active transport:
Neurons and glia
In order to get rid of EAA’s, ___ convert the EAA’s to glutamine and release it into the ECF
Glia
-Neurons take glutamine up and convert it back to glutamate
What are some neural functions of NO?
- Long-term potentiation and memory
- Cardiovascular and respiratory
__ is an EAA derived from alpha-KG; its metabolic and NT pools are strictly separated
Glutamate
Describe what happens in an area most directly affected by ischemia (anoxic core):
With O2 deprivation, cells are unable to meet metabolic needs —> DEPOLARIZATION of membrane
-Within 4 minutes: ATP levels within neurons to 0–> Na/K ATPase ceases and Vm depolarizes
Describe levels of EAA during CNS ischemia/excitotoxicity:
- High levels of EAA –> Excessive release of EAA into post-synaptic density; EAA re-uptake is Na+ dependent
- NMDA receptor activation –> Ca2+ influx
When CNS ischemia has occurred, increased [Ca2+] initiates these 4 activating events:
- Activation of PLA2
- Activation of calcineurin (phosphatase)
- Activation of mu-calpain (protease)
- Activation of apoptotic pathway
During CNS ischemia, PLA2 is activated –> release of ___ from the membrane –> causes physical damage to membrane –> arachidonate acts at ___ receptor on ER –> Release of __ from intracellular stores –> In the ER, “unfolded protein response” stops making protein, activation of ___ kinase, mitochondria function impaired
- arachidonate
- ryanodine
- Ca2+
- eIF2-alpha
During CNS ischemia, activation of mu-calpain (protease) results in ___
-Proteolysis–> spectrin (more structural damage to cell), eIF4G (eukaryotic induction factor 4G-protein synthesis), others (metabolic impairment)
During CNS ischemia, activation of calcineurin (a phosphatase) leads to ___
-Activation of Nitric Oxide Synthase –> INCREASE NO SYNTHESIS
During CNS ischemia, the disruption of mt and ER function increases free ____
Cytosolic calcium
As mt membranes are disrupted, apoptotic pathways are activated. Activation of cytochrome C and caspase 9 leads to ____
Activation of Caspase 3 –> proteolytic enzyme, apoptotic
During reperfusion injury, Kinases take ATP –> ADP + PO4. This phosphorylation further modifies enzyme action. The phosphorylation of ___ leads to a decreases in protein synthesis and activates caspase __, which increases apoptotic signaling
- eIF2alpha kinase
- 3
During reperfusion injury, in high quantities ___ contributes to edema by damaging capillary endothelial cells
NO
Activation of NMDA receptors (ionotropic) opens a channel that allows primarily ___ to enter the cell
Ca–> a channel wide enough to allow Ca to enter will also allow Na to enter
Increased __ ion inhibits the opening of the channel on an NMDA receptor
Hydrogen–> on the EC side of the complex
The PCP binding site on an NMDA receptor is located where and what does it block?
Inside of the channel and blocks the Ca2+ current
How is Mg2+ kicked out of the inside of the NMDA receptor?
- Mg2+ is bound to the site at resting membrane potential
- The Mg2+ will leave this site and allow Ca2+ current with depolarization of the cell
AMPA receptors (Non-NMDA) are activated by exogenous AMPA, as well as glutamate or aspartate. It allows primarily ___ influx
Na+
The Kainate receptor (non-NMDA) is opened by exogenous kainate (but not AMPA) as well as glutamate and aspartate. Depending on sub-unit composition, this channel may allow some ___ in the cell, but is still primarily a ___ channel
- Ca2+
- Na+
___ is a rare condition in which severe, intractable seizures develop in a child. Accompanying these seizures is brain damage that ends up destroying 1 hemisphere of the brain. The only known treatment is surgical removal of the affected hemisphere.
Ramussen’s encephalopathy –> Abs directed against the metabotropic receptor have been found in some humans suffering from the condition
Describe the glutamate-glutamine cycle in astrocytes:
Astrocytes take up the glutamate and convert to glutamine via glutamine synthetase (requires ATP) –> Glutamine is released back into the EC space for neurons to take back up –> In neurons, it is converted back to glutamate
-Disruption of this system decreases the amount of glutamate released by neurons
___ constitute the major excitatory system in the brain and SC of humans
EAA
EAA at non-NMDA receptors are all/most ___ in the spinal cord (generally excitatory synaptic transmission)
Primary afferents
EAA at NMDA receptors are found throughout the CNS, but most attention paid in the ___ and related areas.
Hippocampus
EAA at NMDA receptors are believed to be involved in (functionally):
- producing long-term changes in synaptic strength via a process known as long-term potentiation
- memory
- learning
EAA at metabotropic recptors are widely distributed throughout the CNS. Many are presynaptic and serve to modify EAA release. The general effect is a __ in synaptic excitability (often a long-term effect).
Decrease
EAA at metabotropic receptors are believed to be involved in the synaptic plasticity associated with ___
Learning and memory (along with NMDA receptors)
Describe the effects of NO relative to the production of cGMP:
- In smooth muscle, causes relaxation
- When made by endothelial cells, it acts on smooth muscle cells to cause relaxation (cGMP)
-In the CNS, linked to changes in pre-synaptic neuron related to long-term potentiation or depression –> respiratory control, CV control, memory/learning
What is the major NON-neural effect of NO?
NO is one of the major controls of cerebral vasculature: blood flow almost completely controlled by local activity
-NO is the mechanism for dilation
In high enough concentrations, describe the effects of NO:
- Free radical production–> peroxidation of membrane lipids, rendering the membrane less fluid and damaging the membrane
- Inappropriate protein nitrosylation –> changes the functioning of the protein, often inhibiting it
Excitotoxicity can be caused by:
- Cerebral ischemia/stroke
- Hypoxia or anoxia (strong evidence)
- Mechanical trauma to the CNS (strong evidence)
- Hypoglycemia
