17 Chemical Messengers and Excitotoxicity - M/A Flashcards
1
Q
How do you identify if a neurotransmitter is fast or slow acting?
A
By the type of channel it activates; (ionotropic = fast, metabotrophic = slow)
2
Q
Ionotropic receptors are what?
A
Gated ion channels that are opened by binding of ligand = ions flow; results in a quick effect
3
Q
Metabotropic receptors are what?
A
receptors that work through a 2nd messenger system when activated = slow effect; i.e GPCRs
4
Q
What are the 4 major types of receptor classes?
A
GPCRs, RTKs, Ligand-gated ICs, NTFRs
5
Q
How is the signaling of neurotransmitters (NTs) terminated?
A
- reuptake
- enzymatic degradation
- diffusion away from the synapse
- accumulation in glial cells
6
Q
What are the possible effects that an NT can have on its target receptor?
A
stimulator, inhibitor, or modulator
7
Q
What ion is required for the exocytosis (release) of an NT from a presynaptic neuron?
A
Ca2+
8
Q
What are the 5 major biogenic amines?
A
- Epi
- norepi (NE)
- Dopa (DA)
- Histamine
- Serotonin (5-HT)
9
Q
What amino acid are catecholamines (Epi, NE, and Dopa) derived from?
A
tyrosine
10
Q
What is the rate-limiting step in catecholamine synthesis?
A
tyrosine –> L-dopa
11
Q
Which catecholamine is L-dopa converted into?
A
Tyrosine –> L-dopa–> Dopa– >NE
12
Q
What enzyme is needed to convert NE –> Epi?
A
phenylethanolamine N-methyltransferase (PNMT)
13
Q
What are the 2 major enzymes in catecholamine production?
A
tyrosine hydroxylase and PNMT
14
Q
That is the sequence of catecholamine synthesis
A
15
Q
Where does the conversion of dopamine –> NE occur?
A
in vesicles called chromaffin granules
16
Q
Where is NE –> Epi?
A
cytosol
17
Q
What moves Epi from the cytosol into vesicles?
A
VMATs
18
Q
What are COMTs and MAOs?
A
enzymes that inactive catecholamines convert them into VMA
19
Q
What products of catecholamine metabolism is used to measure catecholamine production?
A
VMA
20
Q
Where are NE producing neurons found?
A
Locus coeruleus = crucial to waking up/awareness; projects to almost all areas of CNS
21
Q
Where is Epi primarily released?
A
adrenal medulla
22
Q
Where is dopamine made in the CNS?
A
substantia nigra (black substance) and ventral tegmental area of brain stem
23
Q
Where does the substantia nigra project to?
A
striatum (lentiform nuclei & caudate nuclei)
24
Q
Where does the ventral tegmental area project is DA fibers to?
A
prefrontal cortex and parts of the limbic system
25
What are the 4 major systems that use DA?
1. substantia nigra = motor
2. mesolimbic = VTA --\> Nucleus accumbens
3. mesocortical = VTA--\> frontal cortex
4. tuberinfundibular = hypothalamus --\> anterior pituitary (prolatin suppression)
26
where is histamine made in the CNS?
the tuberomammillary nucleus (TMN) of the posterior hypothalamus; project throughout brain
27
What cognitive state is histamine associated with?
wakefulness
28
How does histamine down regulate itself?
activation of H3 receptors on presynaptic neuron says there is enough histamine
29
Diamine oxidase degrades what?
histamine
30
What nuclei make serotonin (5-HT)
raphe nuclei of the brainstem
31
What amino acid is 5-HT derived from?
tryptophan
32
What is the synthesis pathway for serotonin?
1. tryptophan --\> 5-HTP via ***Tryptophan hydroxylase***
2. 5-HTP--\> serotonin via ***5-HT decarboxylase***
33
What is the rate-limiting step in serotonin synthesis?
tryptophan --\> 5-HTP via tryptophan hydroxlase
34
What is the function of serotonin?
control attention and mood; involved in depression
35
How is serotonin metabolized?
MAO upon reuptake; so cytosol and vesicles
36
What type of receptors does serotonin activate?
* 6 isoforms of metabotropic receptors
* 1 isoform of ionotropic receptors (type 3 receptor)
37
Where are Cholinergic NTs made in the CNS?
1. Pons/midbrain (pontomesencephalotegmental complex)
2. nuclesu basalis (frontal cortex)
3. septal nuclei (limbic system)
38
What cognitive tasks are cholinergic/ACh secreting neurons important for?
Learning and memory
39
What are the CNS functions of Ach?
1. consciousness (arousal/wakefulness)
2. voluntary motion
3. initiation of REM
40
Is Ach an inhibitory or excitatory NT
mainly excitatory
41
What moves Ach from the cytosol into vesicles?
VAchT (sometimes seen as VAT)
42
What enzyme breaksdown Ach?
acetylcholinesterase (AChase)
43
What type of receptors are activated by Ach?
1. Nicotinic (ionotropic)
2. muscarinic (metabotropic)
44
There are 5 isoforms of Muscarinic (Ach) receptors. Which isoforms use Gq and Gi GPCRs?
* Gq = M1, M3, M5
* Gi = M2, M4
45
Which isoform of muscarinic receptors are found in the CNS?
M1 (Gq --\>IP3 & DAG --\> increased Ca2+)
46
Where are Ach nicotinic receptors found?
NMJ, autonomic ganglia, and CNS
47
What are the 2 main inhibitory amino acids?
GABA & glycine
48
Where is GABA main found? what type of neurons?
cortical & cerebellar inhibitory interneurons
49
Which amino acid is GABA derived from?
glutamate (which is excitatory; oh the irony)
50
What are the 2 major GABA receptor isoforms?
1. GABAa = opens Cl- ionotropic channels
2. GABAB = metabotropic --\> increased K+ efflux
51
Which GABA receptor is the most common, is ionotropic and conducts chloride?
GABAa
52
Which GABA receptor is metabotropic and results in intracellular increased K+
GABAb
53
What drugs target and augment GABA receptors?
***_Benzodiazepines,_*** barbiturates & ethanol = sedative action
54
What is the major inhibitory NT in the spinal cord?
glycine = action on glycine receptor
55
What enzyme converts Glutamate into GABA?
Glutamate decarboxylase
56
What is the major categorical difference between monoamines, cholinergic, & amino acid NTs vs opioids?
* monoamines, cholinergic, and amino acids NTs are ***_small molecules_***
* Opioids are ***_neuropeptides_***
57
What are the 3 opioid peptides that we care about?
endorphins, enkephalins, and dynorphins
58
Which opioid peptide is derived from POMC and targets mu receptors?
endorphins
59
What are the effects of Mu receptors?
* analgesia & sedation
* respirator depression
* constipation
* euphoria
* increased GH & prolaction
60
What is the mechanism behind Mu receptors?
Increases K+ efflux --\> hyperpolarization
61
What are the effects of Kappa opioid receptor activation?
* analgesia & sedation
* diuresis
* miosis
* dysphoria
62
What is the mechanism that Kappa & Delta opioid receptors use to elicit their effect?
decrease Ca2+ influx
63
What are the effects of delta opioid receptors?
analgesia
64
Where are nociceptin receptors found and what is their effect?
found throughout brain and produces anxiety, depression & tolerance to Mu-opioid agonists
65
What is excitotoxicity?
- Proposed mechanism to explain continual neuron death after an ischemic event.
- Based on the idea that overstimulation of EAA system can cause cell death even in neurons not directly involved in the ischemic event.
66
Where do we see evidence of excitotoxicity existing?
* Cerebral ischemia or stroke
* Hypoxia
* Anoxia
* Mechanical trauma to CNS
* Hypoglycemia
* **_Epilepsy_**
67
What are the areas most affected by the ischemic event (anoxic core)?
* Oxygen deprivation
* Cells unable to meet metabolic needs
* Depolarization of membrane
68
Within minutes of an ischemic event (anoxic core) of a neuron, what is seen?
* ATP levels fall to 0 inside the neurons
* Na+-K+-ATPase function ceases
* Cell depolarizes
* Leads to action potential and release of neurotransmitters including EAAs
69
After minutes of an ischemic event occurring, high amounts of EAAs accumulate in the synapse. Why?
* Excessive EAA released
* EAA re-uptake is Na+ dependent is decreased d/t Less Na+ around in synaptic cleft
* NMDAR activation is Ca2+ dependent
* Less Ca2+ around in synaptic cleft
70
When CNS ischemia has occurred, increased intracellular [Ca2+] initiates excitotoxicity. How does it do this? (4)
1. Activation of phospholipase A2
2. Activation of calcineurin (phosphatase)
3. Activation of Mu-calpain (protease)
4. Activation of apoptotic pathway
Excess activation of these enzymes disrupts normal cellular function
71
Regarding CNS ischemia, describe the activation of phospholipase A2.
* Release of arachidonate from membrane and causes physical damage to the membrane
* Arachidonate acts at **_ryanodine receptor_** on ER
* Release of Ca2+ from intracellular stores
* ER: “unfolded protein response” – stops making protein
* **_Activation of eIF2α-kinase_**
* Mitochondria: impaired function
72
Regarding CNS ischemia, describe the activation of μ-calpain (protease).
Proteolysis
• **_Spectrin_** (more structural damage to cell)
• **_eIF4G_** (eukaryotic induction factor 4G – protein synthesis)
• Others – metabolic impairment
73
Regarding CNS ischemia, describe the activation of calcineurin.
Phosphatase
•Among other things, activates **_NOS_**
•Increases NO synthesis
74
The activation of the three (3) enzymes (phospholipase A2, Mu-calpain, calcineurin). during CNS ischemia, causes a disruption of mitochondrial and ER function, which further increases what?
**free cytosolic calcium**
75
During CNS ischemia, what does an increase in free cytosolic Ca2+ lead to?
Increase in mitochondrial membrane disruption, and **apoptotic pathways** are activated.
76
Describe the basic idea regarding reperfusion injury. (9)
1. CNS ischemia lead to an apoptoic neuron.
2. Blood is reperfused to the area (no longer ischemic), but neuron is no longer "normal" since apoptosis started.
3. Much of the new O2 will end up as free radicals somewhere (peroxides)
4. Increase in O2 leads to production of ATP
5. But enzymes currently activated in necrotic neuron aren't "normal"
6. Kinases take ATP --\> ADP + PO4
7. Phosphorylation, further modifying enzyme action
8. Phosphorylation of **_eIF2α kinase_** leads to a decrease in protein synthesis & **_activates caspase 3_**, which increases apoptotic signaling
9. Nitric oxide adds to the cascade by contributing to edema via damage to capillary endothelial cells and vasodilation
77
Is there any way to stop reperfusion injury from happening?
Preventing this cycle is **difficult at best**
To date, most experimentally successful treatments are pre-treatments that focus on the NMDA receptors.
78
What is the 5-HT2a receptor associated with?
smooth muscle contraction
79
What is the 5-HT3 receptor associated with?
Vomiting
80
What is the 5-HT6 receptor associated with?
high-affinity for several antidepressants (SSRIs/SNRIs)
81
What is the 5-HT2c receptor associated with?
role in controlling normal body weight and preventing seizures
82
Which serotonin receptor uses a Gi receptor mechanism?
5-HT1
83
Which serotonin receptor uses a Gq receptor mechanism?
5-HT2
84
From what molecule are enkephalins derived from?
proenkephalin
85
What receptor is the cause of respiration depression during opioid o/d?
Mu opioid receptor
86
people on chronic opioid treatment are more likely to have frequent constipation, why?
stimulation of Mu-opioid receptors
87
What are the 2 main endocannabinoids?
Anandamide & 2-AG
88
What is unique/atypically about endocannabinoids?
not stored in vesicles, released from pre-synaptic terminal, have retrograde actions
89
What is the most abundant cannabinoid receptor in the brain?
CB1 receptors
90
What kind of GPCR are CB1 receptors
G i = reduce Ca2+ influx or enhance K+ efflux
91
Wher are CB 1 receptors found on neurons?
presynaptic terminal = allow for retrograde action
92
What are CB1 receptors associated with in the spinal cord?
modulation of nociception
93
What are CB1 receptors associated with in the neocortex?
protects against excitotoxicity
94
What is important about CB2 receptors?
* anti-inflammatory properties systemically
* found on microglia in brain (uncertain of role)
95
What are the 2 primary excitatory amino acids?
* glutamate (Know this one)
* aspartate
96
From which kerbs cycle intermediate is glutamate derived from?
alpha-ketoglutarate
97
What receptors types are associated with glutamate receptors?
* Metabotropic
* ionotropic
* NMDAs
* AMPAs & KAs
98
What are the two major glutamate ionotropic receptors we care about?
NMDA & AMPA
99
What is the functional difference between AMPA and NMDA receptors
* AMPA = fast (Na/K+ flux)
* NMDA = slow (voltage gated and Ca2+ flux)
100
Why do NMDA receptors have a slow response to activation?
Are voltage-gated (Mg2+ blocking channel)
101
What modulators can bind to NDMA receptors?
1. glycine (required for opening)
2. Mg2+ (blocker/plug)
3. PCP (blocker)
102
What amino acid is a co-agonist and is required for the activation of NMDA receptors?
glycine
103
What is the role of Mg2+ in regards to NMDA receptors?
sits inside channel to block it; removed when RMP is above ~60mV
104
What are the roles of AMPA and NMDA receptors in regards to EPSPs?
* AMPA = fast depolarization
* NMDAs = determine duration of depolarization
105
Where are AMPA and NMDA receptors typically found?
on post-synaptic neurons typically
106
Which post-synaptic receptor associated w/ EAAs is associated w/ Na+ influx
AMPA
107
Which post-synaptic receptor associated w/ EAAs is associated with Ca2+ influx
NMDAs
108
What class of drugs bind to and inhibit AMPA receptors? What other class of receptors are affected by the same class of drugs?
Benzodiazepines; GABAa receptors
109
What type of neurons are non-NMDA receptors (AMPAs) associated with?
Primary afferents & UMNs
110
What type of neurons are NMDARs associated with?
* Long-term synaptic changes (LTP)
* learning
* memory
111
What are neurons/cognitive tasks are Metabotropic receptors associated with?
* learning
* memory
* motor systems
112
How are EAAs cleared from the synaptic cleft?
* reuptake by neurons
* glial cells
113
Why is nitric oxide (NO) unique as an NT?
* not stored in synaptic vesicles
* release is Ca2+ independent
* diffuses through membranes
* retrograde and anterograde signaling
114
How do NMDARs regulate NO?
influx of Ca2+ binds to calcineurin which activates NOS --\> NO production
115
What are the neural effects of NO?
* smooth muscle relaxation
* role in memory
* enhances NT release in CNS
* can lead to excitotoxicity!!!
*
116
Here is another image regarding CNS ischemia and what an increase in cytosolic Ca2+ can lead to.
