EAA excitotoxicity and neurotransmitters Flashcards
what is the most important excitatory nuerotransmitter in the brain that is widely distributed in the CNS
EAA
- glutamte
- aspartate
- *metabolic and NT pools are separated
what type of receptors do EAAs use ? how do they function ?
- ionotropic- NMDA receptor and non-NMDA receptor (AMPA and kainate)
- metabotropic - groups 1 (Gq) and 2 and 3 (Gi)
what makes the NMDA receptor both ligand and voltage gated?
-Mg2+ ion binding site in addition too the EAA ligand binding site
explain the details of the NMDA receptor
- ionotropic- NMDA receptor
- allow channel influx of calcium when endogenous Asp or Glu bind, or exogenous NMDA
- has glycine (cotransmitter) binding site which binds glycine needed to open channel
- has Mg2+ binding site in the channel which binds Mg2+ and blocks the channel at RMP preventing calcium influx. must depolarize the membrane to move Mg out the way by quick EPSP from non-NMDA channel opening and Na+ influx
- PCP binding site in the channel also blocks calcium influx when exogenous PCP is ingested or ketamine to a certain extent
*delayed but long lasting EPSP
explain the details of the non-NMDA receptor
- ionotropic
- allow channel influx of Na+
- produces quick and short EPSP
- two types
- AMPA
- activated by exogenous AMPA or endogenous Glucoses and Asp
- benzodiazepine binding site preventing Na influx and increasing sedative effect - kainate
- opened by Asp and Glu and moves in both Na+ and Ca2+
what is the differences between non-NMDA and NMDA receptors for EAA
NMDA
- Ca2+ influx
- delayed long EPSP (bc must depolarize membrane and move Mg out way)
- activated second by the quick EPSP and depolarization of the non-NMDA receptor
non-NMDA
- Na+ influx
- rapid short EPSP
what is the function of the non-NMDA and NMDA receptors
non-NMDA
- primary sensory afferent
- upper motoneurons
NMDA
- short/long term memory
- synaptic plasticity
what are the functions of the groups of metabotropic EAA receptors pre and postsynaptically ?
pre
-control NT release
post
- learning, memory, motor system
explain the mechanism of action of the metabotropic EAA receptors
- EAA (Glutamate) in blood binds to glial cell receptor which converts glutamate to glutamine
- glutamine is sent to the presynaptic cell and converted back to the EAA glutamate
- the EAA glutamate will be released and bind to the postsynaptic cell
- influx of calcium and membrane depolarization
- calcium binds calcenurin which activates NO synthase to convert arginine to NO and citruline
- NO diffuses back to presynaptic cell and increases release of NT
- Group 1 = Gq (increase IP3, DAG, calcium)
- Group 2/3 = Gi (decrease CAMP)
what are the neural functions of NO ? non neural
neural
- long term potentiation of memory in hippocampus and cerebellum
- cardiovascular and respiratory control via pons and medulla
non-neural
-important in innate immunity bc of ability to vasodilator vasculature
what is the downside of NO
- short half life
- produces free radicals
- toxic to neurons in high amounts
what is excitotoxicity
-overstimulation of the EAA system from ischemia is brain leading to death of exposed and non-exposes neurons
describe the steps of exitotoxciity
Step 1 : membrane depolarization
-ischemia leads to rapid O2 drop and ATP production stops. Na/K ATPase function decreases and membrane depolarizes
step 2: action potential
-depolarization opens voltage gated sodium channels and sodium influx produces an action potential
step 3: releasing the EAA
-the AP reaches the presynaptic terminal and induces NT (EAA) release. bc of widespread EAA use, large amounts of EAA are released all over the brain
step 4: Post-synaptic cell calcium increase
-non-NMDA receptors activated and depolarize membrane to allow Mg2+ removal and NMDA activation for Ca2+ entry in cell
The uptake of EAA is dependent on ____ that becomes dysfunctional during an ischemic event
secondary active transport of Na+
Na/K ATPase
consequences of high intracellular calcium
- increased Phospholipase A activity
- initiates arachidonic acid release which physically damages membrane and acts as second messenger for calcium release, unfolded protein production, elf2a-kinase activation, mitochondrial dysfunction - mu-calpain activation
- strucutural protein and elf4G proteolysis = metabolic and structural neuron impairment - calcinurin activation
- increases NO production which causes free radical production and vasodilation that leads to increased swelling (symptom worsening) - apoptotic pathway
- mitochondrial dysfunction leads to release of Cytochrome C and caspase 3 and 9
- caspase 3 is pro-apoptotic proteolytic enzyme
what are the effects of reperfussion of O2 back to brain after an ischemic event in which induces excitotoxicity
- changes in the brain that occur initially from excitoxcity cause change in way the brain cells use O2
- bc the mitochondria has released its content and is dysfunctional, the oxygen can not be used and therefore turns into free radicals (some ATP can be made but more free radical production)
- kinases will dephosphorylate the few ATP made and phosphorylate ELF2a kinase.
- leads to further caspase 3 activation and more apoptosis
what part of the brain “makes” neurotransmitters
the cell bodies (the nucleus)
- *i.e. raphe nucleus and serotoninergic neuron cell bodies which makes serotonin
- *the post-synaptic cell is what responds to the NT made and released
what NT is responsible for vommiting
serotonin
-made in raphe nucleus
what is the cell body location of histamine production? what’s its function? receptor ?
- tubermamillary nucleus
- waking
- H1/H2 metabotropic receptor
the neuronal cell bodies that make Ach are located in
the striatum of the basal ganglia
- putamen
- caudate
the M1/M4/M5 MAchR receptors for Ach are located where and have what function
M1- Gq - neuronal
M4- Gi - presynaptic striatum of basal ganglia
M5- Gq - cerebrovasculture, dopaminergic neurons of basal ganglia
changing the subunits of the NAchR channel has what affect
change the properties of the channel and sometime can allow more calcium entry into the cell
what are the 2 major inhibitory NTs
GABA and glycine
-more GABA the higher in the CNS you go (most in cortex and least in spinal cord)
how is GABA made? transported? and removed from synapse ?
-made from glutamate via GAD
-transported in vesicles via VGAT
-removed via GAT
(GAT 1 on presynaptic terminal)
(GAT 2 on glial cells surrounding synapse)
what is the difference between the GAT 1 and GAT 2 pathway
GAT 1 - on presynaptic terminal
-takes up GABA and recycles it back into vesicles
GAT 2- on glial cells (astrocytes)
-takes up GABA, makes glutamine, moves glutamine to pre-synaptic terminal, and recycles back to GABA
GABA (A) vs GABA (B) receptors
A - extra-synaptic
- ionotropic (Cl- conductance)
- in adults- moves Cl - and hyperpolirzes membrane making an IPSP
- in children - moves Cl- out and depolarizes membrane
- potientiated by benzodiazepine, ethanol, steroids, general anesthetics
B - pre and post synaptic
- metabotropic (Gi/Go coupled)
- Gi = K+ channel activation (GIRK)
- Go= Ca2+ channel inhibition
- pre = NT release regulation
- post = post cell inhibition
location of glycine vs GABA
GABA is more higher in CNS (>cortex)
glycine is more lower in CNS (> spinal cord)
effect of stychnine
binding of Glycine receptor and blocking it therefore canceling inhibition and causes convulsions
function of glycine
-Cl- conductance and IPSP production via GlyR ionotropic receptor
purines: location ? function ? transporter? receptor?
- ADP/ATP/ adenosine
- all over CNS
- transport = VNUT
- receptor = P1, P2Y, P2X
P1- adenosine receptor that inhibits neuron, and induces sleep. also inhibits NT release
-P2X (ATP receptor) inotropic -moves Ca and Na in
-P2Y (ATP/ADP receptor) Gs/Gq coupled
P2s = learning and memory, modification of locomotor pathway
endorphins, enkephalins, dynorphins, and nociceptin are peptides in what family
opioids (peptide NT)
*all take away pain except nociceptin causes pain
opioid NT: location ? function? receptor ?
- basal ganglia
- modification of nociceptive input and mood/affect (addiction)
- precursors: promelanocortin, pro-enkephalin, pro-dynorphine, orphanin FQ
- mu receptor (increases K efflux) ** analgesia (pain relief) , respiratory depression, euphoria, constipation, sedation (heart RACES from opioids)
- kappa receptors (decreases Ca) **analgesia and dysphoria
- delta receptors (decreases Ca) ***analgesia
- all receptors are metabotropic serpentine and activate Gi/Go coupled path
what are the 2 types of endogenous endocannabinoids ? exogenous ?
- anandamide
- 2 AG
-THC
endocannabinoids: location? synthesis ? receptor ?
- BROAD : basal ganglia (mood) ; spinal cord (nocicpetion modulation) ; cortex (nueroprotection)
- from arachidonic acid in presynaptic terminal
- CB1 receptor - reduces EAA and GABA release via Gi mechanism
- CB2 receptor - immune function (anti-inflammatory) and can decreases B-amyloid in brain
