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Chemical Messengers And Excitotoxicity Flashcards

1
Q

What are the presynaptic channels?

A

Presynaptic voltage gated gated calcium channels

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2
Q

What do presynaptic voltage gated calcium channels do?

A

Allows calcium to come in and bind at docking proteins

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3
Q

What are inotropic receptors?

A

Ligand gated ion channel

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4
Q

What are metabotropic receptors?

A

Activated G protein

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5
Q

What are IPSPs?

What is this assoc. w/?

A

Small, localized hyperpolarizations

Chloride entry

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6
Q

What are EPSPs?

What is this assoc. w/?

A

Small, localized depolarization

Assoc.w/ Na or Ca entry

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7
Q

What is temporal summation?

Where does it occur?

A

Multiple IPSPs or EPSPs elicited from DIFFERENT synapses

Post synaptic cells

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8
Q

What is spatial summation?

A

Multiple IPSPs and EPSPs elicited from REPETITIVE activation at the SAME synapse

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9
Q

What happens when a cell reaches threshold?

A

An action potential occurs

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10
Q

What kind of receptor is a

Nicotinic cholinergic R.?

A

Ligand gated ion channel (ionotropic)

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11
Q

How many subunits does a nicotinic cholinergic r. Have?

A

5 subunits

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12
Q

What does a ligand binding a nicotinic cholinergic r. Do?

A

Ligand binds —> conf. Change in pore —> allows ions to enter

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13
Q

What causes the selectively of nicotinic cholinergic rs?

A

Charge of AAs that make up the pore

Size of the pore

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14
Q

What are metabotropic receptors also known as?

A

Serpentine

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15
Q

What codes for metabotropic receptors?

A

1 gene

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16
Q

What produces the variations in metabotropic receptors?

A

Post translational modifications

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17
Q

Have many membrane spanning domains do metabotropic receptors ahve?

A

7

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18
Q

How do metabotropic exert post synaptic effects?

A

Via 1 or more secondary messengers

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19
Q

What are the 2 major types of G proteins associated w/ intracellular domain of metabotropic Rs?

A

Gs

Gi

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20
Q

What do Gs proteins do?

A

Activate adenylate cyclase

Increase production of cAMP from ATP
CAMP interacts with PKA
PKA phosphorylates downstream targets and changes activities

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21
Q

What effects can Gs have?

A

Have effects on protein synthesis at level of gene due to existence of CREB

(cyclic amp response element binding protein)

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22
Q

What does Gi do?

A

Inhibit adenylate cyclase

Decrease cAMP and PKA activation

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23
Q

What does Gq do?

A

Activate phospholipase C

Creates IP3 and DAG

IP3 activates Ca release

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24
Q

What will Ca do?

A

Calcium influences cellular functions

Calcium can work with DAG and activate protein kinase C —> further phosphorylates other proteins

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25
What is the Jak-Stat pathway?
Receptors with tyrosine kinase that activates its dimer when a ligand binds
26
What will activation of Jack stat pathway cause?
Active dimer activates associated kinase and autophosphorylates the receptor then phosphorylates STAT protein STAT dimerizes and goes to nucleus Activates synthesis of various proteins
27
What does retrograde transport cause for rabies?
The 1-3 mo. Long incubation period fo rabies
28
What are the requirements for NTRs?
Neuron making NTR had proper machinery NTR is released in a chemically or pharmacologically identifiable form Exogenous application of NTR reproduces post-syn. Effects Blocking receptor for chemical will block effects of activating pre-synaptic neuron Mechanism for termination exists
29
What is the cholinergic system? Where is it prevalent at?
Any synapse that uses ACh Peripheral nervous system
30
What uses the cholinergic system?
Alpha motor neurons at NMJ
31
What is cholinergic input critical for? What could damage cause?
To being conscious Comatose state or development of Alzheimer’s diseae
32
Where do we see ACh as a NTR in the PNS?
``` NMJ Autonomic preganglionic synapses Parasym. Post-g fibers Symp post-g fibers to sweat glands/muscles Amacrine cells in retina ```
33
Where do we see ACh as a NTR in the CNS?
Striatum | Brainstem arousal
34
How is acetylcholine made?
Acetate CoA + choline Via choline acetyltransferase Gives: acetylcholine
35
What move ach into vesicles for a controlled release?
Vesicular ACh transporter protein (VAChT)
36
How do you break down ACh?
Acetylcholinesterase hydrolyzes ACh back to acetate and choline Choline recycled by presynaptic cell Acetate diffuses away
37
What are the receptors of the cholinergic system?
Muscarine Nicotinic
38
What activates the muscarine receptors for smooth muscle cells and glands? What blocks it?
Muscarine Atropine
39
What are the 5 types of muscarine receptors linked with?
G proteins ``` M1 - Gq M2 - Gi M3 - Gq M4 - Gi M5 - Gq ```
40
Where are M1 Rs? What do they do?
Post -g neurons of ans, broadly distributed Increase IP3, DAG, Ca
41
Where are M2 Rs? What do they do?
Decrease cAMP —> increase K conductance —> hyperpolarization
42
Where are M3 Rs? What do they do?
Smooth muscle of bronchi and vasculature Will increase IP3 and DAG
43
Where are M4 Rs? What do they do?
Presynaptic autoreceptors Control ACh release in Striatum of basal ganglia for motor control Decrease adenylate cyclase —> decrease cAMP
44
Where are M5 Rs? What do they do?
Cerebral vasculature On basal ganglia dopaminergic neurons For motor controls Increase IP3 and DAG
45
What are the 2 subdivisions of nicotinic receptors?
NMJ Neuronal
46
How many subunits make up a nicotinic receptor?
5 subunits each from a different genes Can be homo or heteromeric
47
What is the make up of fetal NMJ AChRs?
2 alpha Beta Gamma Sigma
48
What i the make up of adult NMJ AChRs?
2 alpha Beta Gamma Epsilon The changed subunit allows for more sodium entry and thus a larger conductance
49
What do high ca conductance or neuronal NMJ AChRs. Contribute to? Are these metabotropic or ionotropic?
Ionotropic Learning and memory
50
What are all the NTRs in the monoamine system from?
Created by modifying AAs
51
What are the catecholamines of the monoamine system?
Epi NE Dopamine
52
What are the 5 NTRs making up the Monoamine system?
``` Epi NE Dopamine Serotonin Histamine ```
53
What is epi, NE, and dopamine all derived from?
Tyrosine
54
How do you synthesize catecholamines?
‣ Tyrosine + tyrosine hydroxylate**—> L-DOPA = rate limiting step ‣ L-DOPA + L-DOPA decarboxylase —> Dopamine ‣ Dopamine + enzymes(assoc. w/ intracellular vesicular membrane) —> NE • NE actually synthesized within vesicles ‣ NE leaves vesicle + Phylethanolamine-N-Methyl-transferase (PNMT)*** —> Epi
55
What 4 major pathways use Dopamine?
1. Substantia nigra dopaminergic pathway 2. Mesolimbic dopaminergic pathway 3. Mesocortical dopaminergic pathway 4. Tuberinfundibular pathway
56
What is the role of dopamine? What is damage assoc. with?
Role in producing pleasure and addiciton Parkinson’s disease
57
What is the Mesolimbic dopaminergic pathway? What could alteration of this pathway cause?
From ventral tegmental area to nucleus accumbens Core of pleasure/reward pathways in brains Addiction
58
Where is NE found within the CNS?
Locus ceruleus in upper brainstem (Pons)
59
What is the role of NE?
Waking us up (!!!!!) and awareness Produces inhibition of msucle activity that occurs during REM sleep
60
Where is Epi mostly used?
Used as hormone released by adrenal medulla Not really used in the CNS
61
How are catecholamines stored?
Via vesicular monoamine transporters (VMATs) catecholamines are moved into vesicle where they will be stored (And where NE will be created)
62
Where is VMAT 2?
Neuronal form found in any neuron that releases monoamines | VMAT 1 found in adrenal medulla
63
What do NE and E bind to ?
Alph and beta adrenergic Rs which are mediated by 2nd messenger system
64
What is the second messenger system associated with alpha 1, 2 ,and betas?
Alpha 1 - Gq Alpha 2 - Gi Beta 1,2,3,- Gs QISSS
65
What is the receptor for dopamine?
Dopaminergic receptors with differerent subtypes D1-5
66
Where do we find high concentrations of receptors D1 and D2? What are they involved in?
In regions of brain innervated by substantia nigra Involved in normal control of motion and emotion
67
How are catecholamines removed?
Dopamine, NE and E are all removed via High affinity uptake protein then enzymatic destruction by MAO or COMT
68
What is serotonin derived froM?
Tryptophan
69
Where is serotonin found in brainstem?
Raphe nuclei
70
What is serotonin for?
Critical in mood
71
How is serotonin synthesized?
‣ Typtophan + tryptophan hydroxylase —> Rate limiting step amt. of Trypt. Available and activity level of enzyme determines amt. of serotonin) ‣ ___ + 5-HT Decarboxylase —> serotonin
72
Where are seronergic neurons in the CNS?
Midline raphe nuclei use serotonin as NTR in CNS
73
Serotonin from midline raphe nuclei control what? What could disruption cause?
Attention and mood Depression
74
What are serotonergic receptors associated with?
All associated with G proteins EXCEPT 5-HT-3
75
what is the only ionotropic serotonergic receptor? What is it assoc. w?
5-HT 3 Opens sodium channel Assoc. w/ chemotactic trigger zone in medulla
76
What is the role of 5-HT6?
High affinity for several anti-depressants
77
What is the role of 5-HT2c?
Controlling normal body weight and preventing seizures
78
How is serotonin removed?
Taken up and metabolized by MAO
79
What is histamine derived from?
Histidine
80
What i the role of Histamine
Waking you up (!!!!)
81
What wakes you up? | What keep you awake?
Norepinephrine Histamine
82
Where is histamine made and released in the CNS?
By neurons of tuberomammillary body/nucleus in the posterior thalamus
83
What are the purines that serve as NTRs?
ATP AMP Adenosine
84
What do purine NTRs bind to?
Purinergic receptors
85
What purine is linked to sensation of sleepiness/fatigue?
Adenosine
86
Where is caffeine an antagonist at?
Adenosine receptors
87
How are purine NTRs removed?
Via adenosine Deaminase Converted to inosine and removed via circulation
88
Where does adenosine bind?
P1 receptor
89
What is the function of adenosine?
Sleep induction Feedback inhibition for atp release
90
What are the 5 groups of peptides that bind opioid receptors?
``` Endorphins Enkephalins Dynorphins Endomorphins Nociception ```
91
What are opioids associated with? All except which one?
Pain relief Except for nociceptin
92
Where are opioid NTRs located?
Striatum Hypothalamus Periaqueductal gray Nucleus parabrachialis Raphe nuclei (serotonin also here!)
93
What is the pre-cursor to dynorphins? Where are they found?
Prodynophrins hypothalamus Thalamus Brainstem Retina
94
What will nociceptin produce?
Produces pain
95
What are the 3 receptors of opioid NTRs?
Mu Kappa Delta
96
What does the Mu opioid receptor produce when activated?
Analgesia Respiratory depression Euphoria
97
What does the Kappa opioid receptor produce when activated?
Analgesia | Dysphoria
98
What does the Delta opioid receptor produce when activated?
Analgesia
99
All of the opioid receptors are paired with what and cause what?
Gi Cause inhibition of adenylyl cyclase Mu- increases k out = hyperpolarization Kappa and Delta = decrease Ca in
100
What are the 2 ligands that bind cannibinoid receptors?
Anandamide 2-arachidonoylglycerol
101
What is the endocannibinoid system assoc. with?
Pain relief actions Control of hunger and energy balance May produce neuroprotection
102
What blocks the uptake of endocannabinoids?
Acetaminophen
103
How is anandamide and 2-AG metabolized?
Cyclooxygenase Lipooxygenase
104
What does the CB-1 receptor bind?
Anandamide and 2AG
105
What does CB2 preferentially bind ?
2-AG
106
What is the production of NO tied to?
Activation of excitatory AA receptor - NMDA
107
What are inhibitory AAs?
Glycine | GABA
108
How do inhibitory AAs enact their actions?
Open Cl channel and produce hyperpolarization of membrane
109
What is the major inhibitory AA of the brain?
GABA
110
Where does benzodiazepene work to produce sensation?
GABA Receptors
111
What are the major EAAs in the brain?
Glutamate | Aspartate
112
What is the role of EAAs?
Sensory processing Memory formation Learning Motor control
113
What do EAA Receptors allow for?
Allow ca to enter cell
114
What is excess activation of the EAA system associated with?
Neuronal damage via excitotoxicity
115
What is GABA made from?
Glutamate + GAD
116
Where is gaba localized? Glycine?
GABA - cerebellum and cortex, and retina Glycine: Spinal cord mostly
117
What has the most extra-synaptic receptors? Why?
GABA Bc it is the most inhibitory and will hyperpolarized neurons non specifically for sedation
118
For the EAA system, what is the role of glycine and glutamine?
Glutamine forces Mg off the receptor allowing for docking to occur and glycine is needed for the channel to work:)
119
What is the majority of atp created by neurons used for?
To drive Na/K ATPase pump to help maintain RMP
120
What happens is oxygen or glucose to the brain is blocked? What could cause blockage potentially?
No ATP = no maintenance of RMP = depolarization of brain = AP for a short period of time with NTR release Stroke, drowning, cardiac arrest
121
What will the depolarization of the brain inadvertently cause?
Will produce APs Release NTRs (EAAs) Xs activation - xc Ca entering = Ca binds enzymes and changes activity
122
What can huge amounts of calcium entering a post synpatic cell cause?
Will bind enzymes and change activity Lead to production of NO Release arachidonic acid damaging membrane Hydrolyzed proteins Activate apoptotic enzymes
123
What are the receptors for EAAs? Metabotropic or ionotropic?
NMDA non-NMDA Both ionotropic
124
What do NMDA receptors do? What binding sites do they have?
Open channel for Ca to enter (and Na) Glycine Zinc PCP MG
125
What binding side of NMDA receptors is needed to have an Epsp occur?
Glycine
126
What does the PCP binding site of NMDA receptors do?
Blocks calcium current from inside the channel
127
What does the Mg binding site of NMDA receptors do?
Inside the channel and blocks it
128
What needs to be removed from a NMDA receptor in order for an epsp it occur?
Mg
129
What are two non-NMDA receptors for EAAs?
AMPA r. Kainate R.
130
How are EAAs removed?
By astrocytes and neurons Can use Na dependent 2ndary active transport High affinity system Loss of Na gradient
131
What is Rasmussuen’s encephalopathy? What receptor is it assoc. w?
Severe intractable seizures that develop in a child and can cause brain damage that destroys one hemisphere of the brain NMDA r.
132
How is production of NO tied to activation of the EAA receptor NMDA?
NMDA will allow calcium in Lead to calcineurin activation which will cleave a phosphate group from NOS activating it NOS + arginine = NO
133
What are the actions of nitric oxide?
Induce guanylyl cyclase and form cGMP CGMP will relax smooth muscle, change presynaptic neuron for long term potentiation or depression
134
What are the roles of NO?
Major controller of cerebral vasculature bc it dilates vasculature
135
How is NO removed from the synpase?
No uptake mechanisms bc it is too lipid soluble Hemoglobin could potentially bind but not likely
136
What is the only rate limiting factor of NO?
It’s half life (5 seconds)
137
What kinds of brain damage is excitotoxicity linked to?
Domoic acid poisoning from contaminated muscles Hypoxia or anoxia Cerebral ischemia/stroke Mechanical trauma to the CNS Hypoglycemia
138
What is the sequence of events for excitotoxicity?
1. Ischemic insult 2. Increased intracellular calcium 3. Activation of enzymes by calcium 4. Deranged cellular metabolism 5. Induction of apoptotic pathways
139
What happens as a result of ischemic insult?
Rapid reduction in ATP levels leading to cell depolarizaiton, release of NTRs, activation of Non-NMDA and NMDA receptors, further increase of EAA concentration in synapse
140
What happens once NMDA receptors are activated by the ischemic insult?
Allow xs calcium into cell and voltage gated calcium channels to open
141
After the ischemic insult activates NMDA and that increases intracellular calcium, What effects does calcium have?
Activates Phospholipase A2 Calcineurin —> NO Mu-Calpain(protease) Maybe enzymes for an apoptotic cycle
142
What happens as a result of enzyme activation from calcium? Concerning phospholipase
Phospholipase will act on cell membranes Release arachidonic acid Act on intracellular organelles to cause more Ca release organelles will malfunction (ER will unfold and activate kinases)
143
What happens as a result of enzyme activation from calcium? Concerning mu-calpain
Mu-calpain Damages structural and functional proteins within the cell and inhibits protein synthesis
144
What happens as a result of enzyme activation from calcium? Concerning calcineurin
Activates NOS Produces xc NO
145
How are apoptotic pathways induced during excitotoxicity?
High Ca will disrupt the mitochondrial membrane Releases cyto c and caspase 9 Activates caspase 3 —> major proteolytic enzyme associated w/ apoptosis
146
What happens when one tries to restablish blood flow following an ischemic insult?
Reperfusion injury
147
What happens in a reperfusion injury?
Blood gives oxygen to tissues Neurons take it up and mito. Uses it to make atp But leftover is made into peroxide radicals Peroxide radicals damage lipids, membranes, organelles Blood also delivers blood borne chemicals
148
During a reperfusion injury what are the blood borne chemicals being reintroduced into the brain?
Epinephrine - further depolarizes cell and activates PKA White blood cells- further calcium influx Growth factors - no funct. Organelles to respond to this
149
What happens as a result of calcium activating calcineurin which makes excess NO?
NO will cause vasodilation and smooth muscle relaxation Allows for influx of fluid into damaged areas and causes EDEMA Increased ICP - blood flow compromised - tonsillar and uncal herniations can develop
150
What are some treatments for excitotoxicity?
Block EAA neurotransmission Prevent influx of WBC Uptake Ca Free radical scavenger
151
What are the 2 important things concerning excitotoxicity?
Time (cascade initiated too quickly) Scope of treatments (not wide enough) (Also drugs that would be delivered via blood cannot happen bc of ischemic event) (Cells are damaged and cannot respond to drug)
152
Denervation hypersensitivity occurs when the alpha--motoneuron innervating skeletal muscle is transected. The muscle cell begins to respond to any acetylcholine, whether it is at the neuromuscular junction or not. What is the mechanism for this response?
When there is no synaptic activity, Nicotinic cholinergic R. At motor end plate is released migrates away and may come into contact with Ach from non neural sources becomes activated and produces AP/contraction in sk. M. In absense of intention appear as twitches or fasciculations of muscle rather than organized contractions
153
What contributes to the variations in processes seen after an ischemic event?
Genetic difference of non-NMDA and NMDA receptors that change amt. of cations entering the cell Depressants in s system can lead to better neurological outcomes
154
How do systemic hypothermia and induced comas improve neurological outcomes/survival of people who have different brain injuries?
Metabolism by neurons is decreased Reduced o2 demand Decreased APs = decreased NTR Decreased enzyme activity (caspases) Can use Valium (benzodiazepene) to activate GABA and produce inhibitory effects in brain or act on non-NMDA AMPA receptors to reduce flow thru them and allow for less Na and Ca in cell (hyperpolarizing)

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