Lecture 15: Chemical messengers & Excitotoxicity Flashcards
Where is the CB-2 receptor found and what role does it play?
- Found in brain (microglia, NOT neurons)
- Immune system and gut
- Anti-inflammatory
- In brain, cause macrophages to remove β-amyloid
What is the metabotropic receptor for GABA; what type of G-proteins and the end result?
- GABAB
- Heterodimer G protein (Gq and Gi)
- Increases K+ and decreases Ca2+
- End result = hyperpolarization
What are the excitatory AA’s and what are the inhibitory AA’s?
Excitatory: glutamate, aspartate, taurine
Inhibitory: GABA and glycine
What is the central location (2 of them) in brain for production of ACh?
- Midbrain
- Pons
The NMDA receptor has multiple modulatory sites, whats the function of the PCP site?
- Inside the channel (internal to Mg site)
- Blocks the channel
- PCP only binds if ingested. One of the most common features of NMDA channel blockers is they produce hallucinations
The large amount of EAA’s following an ischemic event causes a huge influx of what ion?
Ca2+
Where does the EAA Aspartate arise from and is documented as the NT where?
- From oxaloacetate
- NT in visual cortex and pyramidal cells
What are the effects of opioid proteins binding Kappa (κ) receptors?
- Analgesia
- Diuresis
- Miosis
- Dysphoria (depressed)
- Inhibits adenylyl cyclase and decrease calcium
The 5-HT3 receptors is special why and what physiologic process is it related to?
- Only ionotropic serotonergic receptor
- Related to vomiting
What are the 2 pharmocological subtypes of non-NMDA receptors?
- AMPA
- Kainate
What are the Metabotropic receptors for ACh in the CNS; related to what?
- Muscarinic receptors
- 5 different subtypes (M1, M2, M3, etc..)
- Second messenger signaling systems
What does the oxygen deprivation associated with ischemia lead to?
- Cells unable to meet metabolic needs, no ATP being produced.
- Na/K-ATPase stops functioning, K+ builds up, cell remains DEPOLARIZED
- Leads to tons of ACTION POTENTIALS
- Also the release of NTs, including EAAs
Dopamine, norepinephrine, and epinephrine are all made from which AA?
Tyrosine
Function in the body of the EAA’s binding Metabotropic receptors?
- Learning
- Memory
- Motor systems
Function of Serotonin in the CNS; metabolized by what enzyme after uptake?
- Controls attention and mood; involved in depression
- Metabolized by MAO enzyme after uptake
POMC makes what important opioid peptide?
β-endorphins
The Metabotropic receptors for EAA are located where?
Both Pre- and Post-synaptic location
A large number of what type of receptors have been found at extra-synaptic locations through-out the cortex and are related to the use of general anesthetics?
- GABA receptors
- Many general anesthetics are postulated to produce anesthesia by activating these receptors
How many different 5-HT (serotonergic) receptors are there; what type of receptor are they (except for one)?
- Seven different 5-HT receptors (5-HT1, 5-HT2, 5-HT3, etc..)
- All are metabotropic, except for 5-HT3 (ionotropic)
Which non-NMDA receptor contains a Benzodiazepine site?
- AMPA non-NMDA receptors
- Benzodiazepine inhibirs response to NT
What type of G-proteins are the 5-HT1 and 5-HT2 receptors associated with?
- 5-HT1 associated with Gi
- 5-HT2 associated with Gq
What kind of receptor is the CB-1 receptor for endocannabinoids; what is the function?
- Decreases NT release
- Interacts with EAA and GABA neurotransmission
- Gi protein-coupled receptor
How does phosphorylation of elF2α kinase contribute to reperfusion injury?
- elF2α kinase leads to decrease in protein synthesis
- Activates caspase 3, which increases apoptotic signaling
The NMDA receptors and non-NMDA receptors are almost exclusively expressed how?
Post-synaptic expression
What receptor does the inhibitory NT glycine act on (ionotropic or metabotropic)?
- Glycine receptor = ionotropic
- Chloride channel
The increased intracellular [Ca2+] following an ischemic event leads to the activation of Phospholipase A2, which has what effect?
- Causes physical damage to membranes and release of arachidonate from membranes
- Arachidonate acts as ryanodine receptor on ER causes release of more Ca2+ from stores including (ER and mito.)
The neurons and glia are able to recycle EAA’s using what kind of transport and what is their affinity for EAA’s like?
- Na+ dependent secondary active transport
- High affinity
The NMDA receptor has multiple modulatory sites, whats the function of the Mg2+ site?
- Mg2+ binding site is inside the channel
- Blocks the channel
- Cell must be depolarized for Mg2+ to leave and for channel to be open
Function in the body of the EAA’s binding NMDA receptors?
- Long-term changes in synaptic strength
- Learning
- Memory
After L-DOPA is produced what are the next steps in the formation of catecholamine NT’s?
- L-DOPA is converted to dopamine
- Third enzyme converts dopamine —-> norepinephrine
- Final step requires norepinehprine to leave vesicle it was made in so PNMT can convert norepi —-> epinephrine
How are the opioid peptides made?
Coded and created via DNA/RNA/Protein synthetic machinery
What are the positive and negative neural functions of NO?
Positive:
- Long-term potentiation and memory
- CV and respiratory control
Negative:
- Leads to production of free radicals
- Kills invading bacteria (but also cells)
Nicotonic receptors are ionotropic and allow for what ions to enter?
- Mainly allow Na+
- Some neuronal forms allow for significant Ca2+ influx!
The NMDA receptor has multiple modulatory sites, what is the glycine site for and why is it so important?
- Glycine serves as a co-agonist
- Presence of glycine REQUIRED for EAA to have effect
- Glycine on own CANNOT open the channel
What are the 3 main opioid peptides?
- Endorphins
- Enkephalins
- Dynorphins
The three catacholamine NT’s are made starting from tyrosine, what is the first step in the pathway (enzyme and product); why is this step important?
- Tyrosine hydroxylase converts tyrosine to L-DOPA
- This is the rate limiting step in the synthesis
What is the relation to the central synapse that use norepi and epi as their NT to the autonomic nervous system?
- Independent of the ANS in the CNS
After Phospholipase A2 disrupts the membrane following an ischemic event we see the “unfolded protein response,” what is this and what gets activated?
- ER stops making protein
- Activation of elF2α-kinase
When the non-NMDA receptor is activated by EAA you get influx of what ion(s)?
- Sodium influx
- Very small amount of Ca2+
What are major locations where opioid peptides are made?
- Basal ganglia
- Hypothalamus
- Parabrachial nuceli and raphe nuclei
The increased intracellular [Ca2+] following an ischemic event leads to the activation of μ-calpain (protease), which has what effects?
- Proteolysis
- Spectrin (more structural damage)
- elF4G (eukaryotic induction factor 4G -prevents protein synthesis)
Where does the EAA glutamate arise from?
- Alpha-KG
- Metabolic and NT pools strictly separated
As oxygen begins to come back after an ischemic event there is risk for reperfusion injury why?
- Neurons are damaged
- Much of the O2 will end up as a free radical somewhere (peroxidase)
- Some will be used to produce ATP, but will be used by kinases, instead of the cell, and more destructive enzymes will be phosphorylated and activated
Activation of non-NMDA receptors causes what kind of epsp?
Leads to a typical epsp
Why are non-NMDA receptors often co-localized at the same synapse with NMDA receptors?
- The non-NMDA receptor is able to bring in Na+, which depolarizes the cell membrane
- This depolarization causes the Mg2+ blocking the NMDA receptor to leave and Ca2+ can now flow through the open channnel
How is Ca2+ and NMDA receptors related to production of NO?
- Influx of Ca2+, which then bind calcineurin
- Activates nitric oxide synthase
- NOS catalyzes the rxn which creates NO from arginine
What are the effects of opioid proteins binding to Mu (μ) receptors?
- Analgesia
- Respiratory depression
- Euphoria
- Sedation
- Constipation
- Inhibits adenylyl cyclase and increase K+ efflux = hyperpolarize
The increased intracellular [Ca2+] following an ischemic event leads to the activation of calcineurin, which has what effect?
- Phosphatase
- Among other things, activates NOS
- Increases NO synthesis!!!
What 3 places do we find GABA?
1) Cerebellum
2) Cortex
3) Retina
*Higher CNS/brain centers*
Where are the ionotropic receptors for ACh; where are they located; how many subunits and what is the relevance of this?
- Nicotinic receptors
- Located at NMJ, autonomic ganglia
- 5 subunits and 16 genes
- Changing the subtype changes the way the channel behaves!
What enzyme breaks down ACh in the CNS and where is this enzyme bound?
- Acetylocholinesterase
- Bound to the post-synaptic cell membrane
What are the steps in the production of serotonin, which is rate limiting?
- Tryptophan —> 5HTP uses tryptophan hydroxylase (rate-limiting)
- 5HTP —> Serotonin uses 5-HT decarboxylase
NE within the CNS is found in a very localized cluster of neurons known as; what is NE crucial for in regards to the CNS?
- Located in locus coeruleus
- Crucial to waking up and alertness
What is the major inhibitory NT of the CNS; critical for what?
- GABA
- Critical for producing conciousness/awarness (brain arousal mechanisms)
- Control of voluntary motion
How do Glia and Neurons work together to recycle EAA’s?
Glia: convert glutamate –> glutamine and then release into ECF
Neurons: take glutamine up and convert it back to glutamate
What is the predominate enzyme for inactivation of epinephrine?
COMT
What is the ionotropic receptor for GABA, what ion is conducted, what potentiation site does it contain?
- GABAA
- Chloride conductance, therefore inhibitory
- Benzodiazepine site potentiates
How does NO add to the cascade and contribute to reperfusion injury and edema?
In high quantity, NO contributes to edema by damagin capillary endothelial cells
ACh in the CNS is crucial for what 3 functions?
- Producing consciousness (wakefullness), but not awarness
- Control of voluntary motion (Basal Ganglia)
- Initiation of REM sleep
What activates the NMDA receptor and when activated what ions is influxed?
- Activated by exogenous NMDA
- Also glutamate and aspartate
- Allows Ca2+ influx
What are the 2 endocannabinoid NT’s?
1) Anandamide
2) 2-Arachidonylglycerol
Histamine is found specificially where in the CNS; main function; which recepots mediate its neuronal effects?
- In the TUBEROMAMMILLARY nucleus of posterior hypothalamus
- Wakefulness
- H1 and H2 mediate neuronal effects
What is the sequence in the production of catecholamine NT’s?
Tyrosine —(tyrosine hydroxylase)—> L-DOPA —> Dopamine —> Norepi —-(PNMT)——> Epinephrine
What are the specific neuronal metabotropic ACh receptors and what does each do?
M1: signals IP3/DAG and increases Ca2+ - Gq
M4: presynaptic autoreceptor; striatum of basal ganglia - decreases cAMP - Gi
M5: cerebrovasculature; dopaminergic neurons of basal ganglia - increases IP3/DAG = Gq
Which serotonergic receptor has a high affinity for anti-depressant drugs?
5-HT6
The poison strychnine has an effect on what receptor?
- Blocks Glycine receptor
- Loss of inhibitory regulation leads to death by respiratory failure following convulsions
What are the 4 major systems in the CNS that use Dopamine and the basic function of each?
- Substantia nigra - motor, damaged in Parkinson’s
- Mesolimbic - VTA to Nucleus Accumbens - Central to pleasure, reward and addiction (cocaine use)
- Mesocortical - VTA to frontal cortex. Attention, high level conciousness
- Tuberinfundibular - hypothalamus to anterior pituitary. Dopamine suppresses release of Prolactin
What are the 2 types of ionotropic receptors for EAA’s?
1) NMDA receptor
2) Non-NMDA receptors
- AMPAR’s
- KAR’s
The precursor molecule proenkephalin makes what 2 important opioid peptides?
- met-enkephalin
- leu-enkephalin
How is the action of GABA limited, enzyme involved?
- Reuptake
- Catabolism by GABA-transaminase
Function in the body of the EAA’s binding non-NMDA receptors?
- Primary afferents
- Premotor (UMN)
What is the main inhibitory NT in the spinal cord?
Glycine
What are the effects of opioid proteins binding Delta (δ) receptors?
- Analgesia
- Inhibits adenylyl cyclase and decrease calcium
*Target for research/future drugs because the only effect is pain relief
Following an ischemic event in the brain there is a high synaptic EAA for what 2 reasons?
1) EAA release excessive
2) EAA re-uptake is Na+ dependent (Na/K-ATPase is non-functional)
Activation of the NMDA receptor leads to what?
- Leads to epsp
- Slower onset (time to remove Mg2+)
- Longer duration (Ca2+)
What AA is GABA derived from and what enzyme makes it?
- Derived from glutamate
- From glutamate decarboxylase (GAD)
Serotonin is located where in CNS and is derived from which AA?
- Neurons located in raphe nuclei
- Derived from Tryptophan
As mitochondiral membranes are disrupted following an ischemic event which cell-death pathway become activated?
- Apoptotic pathway activated
- Cytochrome C and Caspase 9 —> Activates Caspase 3
- Caspase 3 is proteolytic enzyme and apoptotic
