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Neuro I Exam 2 - Pathways > Lecture 15: Chemical messengers & Excitotoxicity > Flashcards

Lecture 15: Chemical messengers & Excitotoxicity Flashcards

1
Q

Where is the CB-2 receptor found and what role does it play?

A
  • Found in brain (microglia, NOT neurons)
  • Immune system and gut
  • Anti-inflammatory
  • In brain, cause macrophages to remove β-amyloid
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2
Q

What is the metabotropic receptor for GABA; what type of G-proteins and the end result?

A
  • GABAB
  • Heterodimer G protein (Gq and Gi)
  • Increases K+ and decreases Ca2+
  • End result = hyperpolarization
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3
Q

What are the excitatory AA’s and what are the inhibitory AA’s?

A

Excitatory: glutamate, aspartate, taurine

Inhibitory: GABA and glycine

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4
Q

What is the central location (2 of them) in brain for production of ACh?

A
  • Midbrain
  • Pons
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5
Q

The NMDA receptor has multiple modulatory sites, whats the function of the PCP site?

A
  • 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
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6
Q

The large amount of EAA’s following an ischemic event causes a huge influx of what ion?

A

Ca2+

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7
Q

Where does the EAA Aspartate arise from and is documented as the NT where?

A
  • From oxaloacetate
  • NT in visual cortex and pyramidal cells
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8
Q

What are the effects of opioid proteins binding Kappa (κ) receptors?

A

- Analgesia

  • Diuresis
  • Miosis
  • Dysphoria (depressed)
  • Inhibits adenylyl cyclase and decrease calcium
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9
Q

The 5-HT3 receptors is special why and what physiologic process is it related to?

A
  • Only ionotropic serotonergic receptor
  • Related to vomiting
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10
Q

What are the 2 pharmocological subtypes of non-NMDA receptors?

A
  • AMPA
  • Kainate
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11
Q

What are the Metabotropic receptors for ACh in the CNS; related to what?

A
  • Muscarinic receptors
  • 5 different subtypes (M1, M2, M3, etc..)
  • Second messenger signaling systems
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12
Q

What does the oxygen deprivation associated with ischemia lead to?

A
  • 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
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13
Q

Dopamine, norepinephrine, and epinephrine are all made from which AA?

A

Tyrosine

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14
Q

Function in the body of the EAA’s binding Metabotropic receptors?

A
  • Learning
  • Memory
  • Motor systems
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15
Q

Function of Serotonin in the CNS; metabolized by what enzyme after uptake?

A
  • Controls attention and mood; involved in depression
  • Metabolized by MAO enzyme after uptake
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16
Q

POMC makes what important opioid peptide?

A

β-endorphins

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17
Q

The Metabotropic receptors for EAA are located where?

A

Both Pre- and Post-synaptic location

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18
Q

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?

A
  • GABA receptors
  • Many general anesthetics are postulated to produce anesthesia by activating these receptors
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19
Q

How many different 5-HT (serotonergic) receptors are there; what type of receptor are they (except for one)?

A
  • Seven different 5-HT receptors (5-HT1, 5-HT2, 5-HT3, etc..)
  • All are metabotropic, except for 5-HT3 (ionotropic)
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20
Q

Which non-NMDA receptor contains a Benzodiazepine site?

A
  • AMPA non-NMDA receptors
  • Benzodiazepine inhibirs response to NT
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21
Q

What type of G-proteins are the 5-HT1 and 5-HT2 receptors associated with?

A
  • 5-HT1 associated with Gi
  • 5-HT2 associated with Gq
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22
Q

What kind of receptor is the CB-1 receptor for endocannabinoids; what is the function?

A
  • Decreases NT release
  • Interacts with EAA and GABA neurotransmission
  • Gi protein-coupled receptor
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23
Q

How does phosphorylation of elF2α kinase contribute to reperfusion injury?

A
  • elF2α kinase leads to decrease in protein synthesis
  • Activates caspase 3, which increases apoptotic signaling
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24
Q

The NMDA receptors and non-NMDA receptors are almost exclusively expressed how?

A

Post-synaptic expression

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25
Q

What receptor does the inhibitory NT glycine act on (ionotropic or metabotropic)?

A
  • Glycine receptor = ionotropic
  • Chloride channel
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26
Q

The increased intracellular [Ca2+] following an ischemic event leads to the activation of Phospholipase A2, which has what effect?

A
  • 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.)
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27
Q

The neurons and glia are able to recycle EAA’s using what kind of transport and what is their affinity for EAA’s like?

A
  • Na+ dependent secondary active transport
  • High affinity
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28
Q

The NMDA receptor has multiple modulatory sites, whats the function of the Mg2+ site?

A
  • Mg2+ binding site is inside the channel
  • Blocks the channel
  • Cell must be depolarized for Mg2+ to leave and for channel to be open
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29
Q

Function in the body of the EAA’s binding NMDA receptors?

A
  • Long-term changes in synaptic strength
  • Learning
  • Memory
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30
Q

After L-DOPA is produced what are the next steps in the formation of catecholamine NT’s?

A
  • 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
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31
Q

How are the opioid peptides made?

A

Coded and created via DNA/RNA/Protein synthetic machinery

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32
Q

What are the positive and negative neural functions of NO?

A

Positive:

  • Long-term potentiation and memory
  • CV and respiratory control

Negative:

  • Leads to production of free radicals
  • Kills invading bacteria (but also cells)
33
Q

Nicotonic receptors are ionotropic and allow for what ions to enter?

A
  • Mainly allow Na+
  • Some neuronal forms allow for significant Ca2+ influx!
34
Q

The NMDA receptor has multiple modulatory sites, what is the glycine site for and why is it so important?

A
  • Glycine serves as a co-agonist
  • Presence of glycine REQUIRED for EAA to have effect
  • Glycine on own CANNOT open the channel
35
Q

What are the 3 main opioid peptides?

A
  1. Endorphins
  2. Enkephalins
  3. Dynorphins
36
Q

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?

A
  • Tyrosine hydroxylase converts tyrosine to L-DOPA
  • This is the rate limiting step in the synthesis
37
Q

What is the relation to the central synapse that use norepi and epi as their NT to the autonomic nervous system?

A
  • Independent of the ANS in the CNS
38
Q

After Phospholipase A2 disrupts the membrane following an ischemic event we see the “unfolded protein response,” what is this and what gets activated?

A
  • ER stops making protein
  • Activation of elF2α-kinase
39
Q

When the non-NMDA receptor is activated by EAA you get influx of what ion(s)?

A
  • Sodium influx
  • Very small amount of Ca2+
40
Q

What are major locations where opioid peptides are made?

A
  • Basal ganglia
  • Hypothalamus
  • Parabrachial nuceli and raphe nuclei
41
Q

The increased intracellular [Ca2+] following an ischemic event leads to the activation of μ-calpain (protease), which has what effects?

A
  • Proteolysis
  • Spectrin (more structural damage)
  • elF4G (eukaryotic induction factor 4G -prevents protein synthesis)
42
Q

Where does the EAA glutamate arise from?

A
  • Alpha-KG
  • Metabolic and NT pools strictly separated
43
Q

As oxygen begins to come back after an ischemic event there is risk for reperfusion injury why?

A
  • 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
44
Q

Activation of non-NMDA receptors causes what kind of epsp?

A

Leads to a typical epsp

45
Q

Why are non-NMDA receptors often co-localized at the same synapse with NMDA receptors?

A
  • 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
46
Q

How is Ca2+ and NMDA receptors related to production of NO?

A
  • Influx of Ca2+, which then bind calcineurin
  • Activates nitric oxide synthase
  • NOS catalyzes the rxn which creates NO from arginine
47
Q

What are the effects of opioid proteins binding to Mu (μ) receptors?

A

- Analgesia

- Respiratory depression

- Euphoria

  • Sedation
  • Constipation
  • Inhibits adenylyl cyclase and increase K+ efflux = hyperpolarize
48
Q

The increased intracellular [Ca2+] following an ischemic event leads to the activation of calcineurin, which has what effect?

A
  • Phosphatase
  • Among other things, activates NOS
  • Increases NO synthesis!!!
49
Q

What 3 places do we find GABA?

A

1) Cerebellum
2) Cortex
3) Retina

*Higher CNS/brain centers*

50
Q

Where are the ionotropic receptors for ACh; where are they located; how many subunits and what is the relevance of this?

A
  • Nicotinic receptors
  • Located at NMJ, autonomic ganglia
  • 5 subunits and 16 genes
  • Changing the subtype changes the way the channel behaves!
51
Q

What enzyme breaks down ACh in the CNS and where is this enzyme bound?

A
  • Acetylocholinesterase
  • Bound to the post-synaptic cell membrane
52
Q

What are the steps in the production of serotonin, which is rate limiting?

A
  • Tryptophan —> 5HTP uses tryptophan hydroxylase (rate-limiting)
  • 5HTP —> Serotonin uses 5-HT decarboxylase
53
Q

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?

A
  • Located in locus coeruleus
  • Crucial to waking up and alertness
54
Q

What is the major inhibitory NT of the CNS; critical for what?

A
  • GABA
  • Critical for producing conciousness/awarness (brain arousal mechanisms)
  • Control of voluntary motion
55
Q

How do Glia and Neurons work together to recycle EAA’s?

A

Glia: convert glutamate –> glutamine and then release into ECF

Neurons: take glutamine up and convert it back to glutamate

56
Q

What is the predominate enzyme for inactivation of epinephrine?

A

COMT

57
Q

What is the ionotropic receptor for GABA, what ion is conducted, what potentiation site does it contain?

A
  • GABAA
  • Chloride conductance, therefore inhibitory
  • Benzodiazepine site potentiates
58
Q

How does NO add to the cascade and contribute to reperfusion injury and edema?

A

In high quantity, NO contributes to edema by damagin capillary endothelial cells

59
Q

ACh in the CNS is crucial for what 3 functions?

A
  1. Producing consciousness (wakefullness), but not awarness
  2. Control of voluntary motion (Basal Ganglia)
  3. Initiation of REM sleep
60
Q

What activates the NMDA receptor and when activated what ions is influxed?

A
  • Activated by exogenous NMDA
  • Also glutamate and aspartate
  • Allows Ca2+ influx
61
Q

What are the 2 endocannabinoid NT’s?

A

1) Anandamide
2) 2-Arachidonylglycerol

62
Q

Histamine is found specificially where in the CNS; main function; which recepots mediate its neuronal effects?

A
  • In the TUBEROMAMMILLARY nucleus of posterior hypothalamus
  • Wakefulness
  • H1 and H2 mediate neuronal effects
63
Q

What is the sequence in the production of catecholamine NT’s?

A

Tyrosine —(tyrosine hydroxylase)—> L-DOPA —> Dopamine —> Norepi —-(PNMT)——> Epinephrine

64
Q

What are the specific neuronal metabotropic ACh receptors and what does each do?

A

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

65
Q

Which serotonergic receptor has a high affinity for anti-depressant drugs?

A

5-HT6

66
Q

The poison strychnine has an effect on what receptor?

A
  • Blocks Glycine receptor
  • Loss of inhibitory regulation leads to death by respiratory failure following convulsions
67
Q

What are the 4 major systems in the CNS that use Dopamine and the basic function of each?

A
  1. Substantia nigra - motor, damaged in Parkinson’s
  2. Mesolimbic - VTA to Nucleus Accumbens - Central to pleasure, reward and addiction (cocaine use)
  3. Mesocortical - VTA to frontal cortex. Attention, high level conciousness
  4. Tuberinfundibular - hypothalamus to anterior pituitary. Dopamine suppresses release of Prolactin
68
Q

What are the 2 types of ionotropic receptors for EAA’s?

A

1) NMDA receptor
2) Non-NMDA receptors
- AMPAR’s
- KAR’s

69
Q

The precursor molecule proenkephalin makes what 2 important opioid peptides?

A
  1. met-enkephalin
  2. leu-enkephalin
70
Q

How is the action of GABA limited, enzyme involved?

A
  • Reuptake
  • Catabolism by GABA-transaminase
71
Q

Function in the body of the EAA’s binding non-NMDA receptors?

A
  • Primary afferents
  • Premotor (UMN)
72
Q

What is the main inhibitory NT in the spinal cord?

A

Glycine

73
Q

What are the effects of opioid proteins binding Delta (δ) receptors?

A

- Analgesia

  • Inhibits adenylyl cyclase and decrease calcium

*Target for research/future drugs because the only effect is pain relief

74
Q

Following an ischemic event in the brain there is a high synaptic EAA for what 2 reasons?

A

1) EAA release excessive
2) EAA re-uptake is Na+ dependent (Na/K-ATPase is non-functional)

75
Q

Activation of the NMDA receptor leads to what?

A
  • Leads to epsp
  • Slower onset (time to remove Mg2+)
  • Longer duration (Ca2+)
76
Q

What AA is GABA derived from and what enzyme makes it?

A
  • Derived from glutamate
  • From glutamate decarboxylase (GAD)
77
Q

Serotonin is located where in CNS and is derived from which AA?

A
  • Neurons located in raphe nuclei
  • Derived from Tryptophan
78
Q

As mitochondiral membranes are disrupted following an ischemic event which cell-death pathway become activated?

A
  • Apoptotic pathway activated
  • Cytochrome C and Caspase 9 —> Activates Caspase 3
  • Caspase 3 is proteolytic enzyme and apoptotic

Neuro I Exam 2 - Pathways (18 decks)

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