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MSKI Final Exam material > Dr. Kruse's Pharmocology of NM junction > Flashcards

Dr. Kruse's Pharmocology of NM junction Flashcards

(100 cards)

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1
Q

ACh synthesis: Choline transporter

A

channel that brings choline into the cell

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2
Q

ACh synthesis: ChAT

A

Choline acetyltransferase enzyme that combines acetyl CoA and choline to form ACh

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3
Q

Alzheimer’s patients have reduced cerebral production of

A

Choline acetyltransferase enzyme (ChAT)

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4
Q

ACh storage: ACh vesicular transporter

A

ATP dependent transporter that immediately shuffles ACH into storage vesicles after ACh synthesis

1K-50K molecules of ACh per synaptic vesicle

a motor nerve terminal may contain over 300K vesicles

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5
Q

ACh release: CA channels

A

open upon depolarization and allow Ca to enter the cell, Ca promotoes vesicle membrane fusion

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6
Q

Ach release: VAMP and SNAPs

A

vesicular and plasma membrane proteins that initiate vesicle-plasma membrane fusion and release of ACh

roughly 125 vesicles rupture per action potential

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7
Q

hemicholinium will block what

A

the choline transporter

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8
Q

the Botulinium toxin will block what

A

Snaps from binding snares (vesicle fusion and release of NT)

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9
Q

Acetylcholinesterase (AChE)

A

enzyme that cleaves ACh into choline and acetate

choline is recycled back into the motoneuron via the choline transporter

endycytosis occurs at the nerve terminal to replenish the number of available vesicles

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10
Q

What does calcium do really?

A

it allows for SNAPS, SNAREs, and VAMPs to take conformations that allow them to interact merge ve

vesicles to the membrane for release of the NT

botulin interferes with this process, thereby blocking acetylcholine

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11
Q

what does botulin toxin ultimately block at the synaptic terminal?

A

Acetylcholine release

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12
Q

Where is AchE located?

A

on the post-synaptic membrane

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13
Q

inhibition of the AChE will do what?

A

it will increase acetylcholine

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14
Q

ACh signaling: two ACh activates two subsets of receptors

A

nicotinic (n) and muscarinic (m) receptors

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15
Q

Nicotinic receptors

A

nAChRs

activated by ACh and nicotine
ligand gated ion channel (Na)
Pre-and-Postjunctional
NMJ: Na increase causes muscle action potential

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16
Q

Muscarinic receptors

A

mAChRs

Activated by ACh and muscarine
G-protein coupled receptor
Pre-and-Post junctional
NOT LOCATED at skeletal NMJ

would find them on smooth muscle (in the GI for example)

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17
Q

who destroys the acetylcholine signal?

A

the acetycholinesterase

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18
Q

which of the two ACh receptors are located on skeletal muscle?

A

the nicotinic

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19
Q

nicotine does what

A

acts on acetycholine receptors

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20
Q

What does the pre-junction nicotinic receptor do?

A

facilitates more vesicle release

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21
Q

what do post-junctional nicotinic receptors do?

A

initiate an excitatory signal

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22
Q

nAChR: location, function, agonist

A

skeletal muscle, contraction, acetylcholine/nicotine = agonist

causes muscle contraction

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23
Q

mAChR: location, function, agonists

A

smooth muscle, contraction, acetylcholine and muscarine

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24
Q

mAChR and cardiac muscle

A

located at the SA and AV nodes, atrium and ventricle

reduce heart rate, reduce conduction velocity
reduce slight contraction, reduce contraction

agonists are acetylcholine and muscarine

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25
Which of the two receptors is a ligand gated channel and which is a 7 transmembrane domain channel?
Nicotinic is a voltage gated channel | Muscarinic uses G coupled proteins
26
mAChRs are
GPCRs
27
How many subtypes of GPCRs are there in mammals?
5 M1-M5 activation leads to a series of intracellular events triffered by second messengers (metabotropic) cellular effects measured in seconds use ACh and muscarine
28
nAChRs are what? what do they do? what is their speed?
ligand gated ion channels allow ions to pass through the channel pore when activated (ionotropic) fastest synaptic event in the nervous system (miliseconds)
29
how many subunits does a the nAChR have?
four distinct subunit assembled as a pentamer surrounded by a central pore where ions pass when activated ACh binding site lies between a and adjacent subunit
30
Ionotropic versus metabotropic channels
Ionotropic: nAChRs metabotropic: mAChRs
31
What kind of amino acids do we expect to line the LGIC?
aspartic acid and glutamic acid (negatively charged) | channels selective to Na, Ca, and K
32
nAChRs antagonists
Atracurium Vecuronium d-tubocuranine Pancuronium
33
What happens when an antagonist interacts with the nAChRs
a signal cant be sent, so its an anesthetic
34
Nm vs Nn
Nm include a, b, d, e and g subunits found ONLY at skeletal muscle motor end plates receptors are pre-post ganglionic Nn include a and b combinations or all a subunit found in the CNS, autonomic ganglia, adrenal medulla receptors are pre-posjunctional
35
Nn
include a and b combinations or all a subunit found in the CNS, autonomic ganglia, adrenal medulla receptors are pre-posjunctional
36
Nm
nclude a, b, d, e and g subunits found ONLY at skeletal muscle motor end plates receptors are pre-post ganglionic
37
NAChR postjunctional activity
Two ACh molecules bind to both binding sites N, K, Ca pass through the channel down concentration gradients the muscle cell is depolarized and an action potential is initiated
38
End plate depolarization
spreads by local currents to activate voltage gated Na channels in the adjacent membrane influx of Na initiates an action potential after threshold is reached (although the motor end plate itself cannot fire action potentials, it depolarized sufficiently to initiate the process in the adjacent muscle membrane
39
does the motor end plate fire an action potential?
no: it depolarizes sufficiently to initiate the process in the adjacent muscle membrane what does flow between adjacent membrane and end plate is a local current
40
Na/K influx/efflux
Na diffuses inwards in large concentrations while K diffuses outwards in smaller concentrations
41
Activation of what receptor will inhibit further ACh release?
mAChR
42
Tetrodotoxin '
Affects the nerve AP Puffer fish toxin (fugu, blowfish) Inhibits voltage gated Na channels, blocks axonal conduction weakness, dizziness, loss of reflexes, hypotension, generalized paralysis. death due to respiratory failure
43
local anesthetics
MOA inhibition of voltage gated Na channels--> inhibition of action potential utilized for pain control lidocain bupivacaine procaine
44
Batrachotoxin
poison dart frog: causes an increase in permeability of Na channels and induces persistent depolarization very toxic
45
Botulinum toxin
clostridium botulinum a group of heterogenous, gram + rod shaped, spor forming obligate anaerobic bacteria 8 types cause human disease ABE, rarely FGH
46
Botulinum toxin action
cleaves SNARE complex involved in exocytosis prevents release of ACh
47
How is botulism classified?
as the acute onset of bilateral cranial neuropathies associated with symmetric descending weakness no sensory deficits except blurred vision foodborne symptoms: vomiting, diarrhea, dry mouth, abdominal pain, nausea has a clinical use to remove wrinkles and prophylaxis of chronic migraine headache
48
Synaptobrevin is the target of
tetanus and Botulinum BDFG
49
SNAP-25 is the target of
Botulinum AVE
50
Syntaxin is the target of
Botulinum C1
51
Which toxin blocks Sodium channels from conducting AP? Which toxin blocks the SNARE complex? Which toxin blocks synaptic vesicle fusion but does so by being internalized and traveling via retroaxonally to the spinal cord?
1) Tetrodoxin 2) Botulinum toxin 3) Tetanus
52
Tetanus act specifically on the
interneurons of the spinal cord: blocks release of inhibitory NTs
53
how does tetanus present?
spasms/muscle spasms
54
Which symptom corresponds to which toxin? 1) Diarrhea, nausea, vomiting, abdominal pain 2) Respiration failure 3) spastics
1. botulism 2. tetrodoxin 3. tetanus
55
NAChR agonists and antagonists
both can prevent synaptic transmission agonist can activate receptor to signal as a direct result of binding to it antagonist binds to receptor but does not activate generation of signal
56
Curare alkaloids
competes with Ach for the nAChR receptors on the motor end plate
57
Curare binding to the nAChR does what
inhibition: flaccid paralysis of skeletal muscle
58
when are curares used?
to inhibit nAChR receptors to induce flaccid paralysis | used during anesthesia to relax skeletal muscle
59
paralysis by curares can be reversed how?
by increasing ACh in NMJ
60
Succinylcholine
depolarizing neuromuscular blocker that binds to nAChR on skeletal muscle and causes depolarization continued depolarization leads to receptor blockage and paralysis
61
What is succinycholine used for?
it induces anesthesia
62
How is succinylcholine's paralytic effects reversed?
time. gotta wait it out.
63
Curate is a ______ blocker; succinylcholine is a ______ blocker
non-depolarizing; depolarizing depolarizing physically blocks the receptors, nondepolarizing prevents them from opening
64
Cholinesterase inhibitors
bind to AChE and block enzymatic activity | AChE breaks ACh down in the NM cleft, so inhibition would increase ACh
65
Clinical use of cholinesterase inhibitor
include dementia associated with alzheimer or parkinson disease, myasthenia gravis, nerve gas, reversal of neuromuscular blockade during anesthesia
66
Agents that effect the muscle AP versus muscle contraction (two in mind)
1) tetrodoxin, blocks outer mouth of sodium channels 2) Dantrolene: inhibits ryanodine receptors in the SR, blocking Ca2+ release clinical uses include malignant hyperthermia spasticity associated with upper motor neuron disorders
67
Dantrolene
inhibits ryanodine receptors in the SR: blocks Ca release used to fight malignant hyperthermia and spasticity associated with upper motor neuron disorders
68
what clinical use does dantrolene have?
fights against malignant hyperthermia and spasticity
69
Vesicles in neurons come from where?
motor neuron cell body in the CN
70
Vesicles for ACh: how do they travel from the motor neuron to the axon terminal?
they travel empty
71
Vesicles for peptide NTs: how do they travel from the motor neuron to the axon terminal?
they travel carrying their full cargo, already synthesized
72
Agents that affect nerve action potentials =
tetrodotoxin | local anesthetics
73
Agens that affect the vesicular acetylcholine release
botulinum toxin tetanus toxin Hemicholinium
74
Agents that affect depolarization
neuromuscular blocking drugs: Curare alkaloids and Succincylcholine
75
Agents that inhibit acetycholinesterase
AChE inhibitors (duh)
76
Agents that affect the muscle action potential
Veratridine (stimulates Na passage into cells and leads to increased nerve exctiability) Tetrodotoxin
77
Agents that affect muscle contraction
Dantrolene
78
Choline enters the neuron how?
through a symporter with Na
79
CHaT
Choline acetyltransferase combines acetyl Co-A and choline together to make ACh, an it is immediately put into vesicles
80
How would inhibiting CHaT be helpful?
it wouldn't be because choline entering the cell is the rate limiting step
81
Vesicle membrane fusion: Snares and Vamps
SNAREs primary role is mediating vesicle fusion
82
v-SNARE
synaptobrevin
83
t-SNARE
syntaxin
84
SNAP-25 does what?
it interacts with synaptobrevin and syntaxin to form the core SNARE complex that brings the vesicle and presynaptic membranes into close contact
85
synaptotagmin
the protein that is effected by Ca2+ rushing into the neuron. synaptotagmin triggers the vesicle fusion and exocytosis
86
alpha-SNAP and ATPase NSF
in synaptic cleft: they dissasemble SNAREs, allowing recycling of vesicle and SNARE proteins
87
What proteins make up the protein complex causing ACh containing vesicles to come near the membrane?
v-SNARE (synaptobrevin) + t-SNARE (syntaxin) + SNAP-25
88
What protein triggers the actual vesicle fusion?
synaptotagmin
89
What proteins breakdown the SNARE complex?
alpha-SNAP and the ATPase NSF.
90
What are the energy requirements for membrane disassembly?
the alpha-SNAP and NSF complex require one ATP
91
mAChRs: how many subtypes exist?
5
92
mAChRs: predominant type found in muscle and cardiac tissue
M2 & M3 = smooth muscle | M2 = cardiac muscle
93
metabotropic
mAChR, GCPR :activation leads to a series of intracellular events triggered by secondary messengers
94
mAChR agonist
ACh or muscarine
95
how do agonist bind?
they bind to the long extracellular amino-terminus and activate intracellular g proteins
96
mAChRs are located...
at the presynaptic ganglia and the smooth neuromuscular junction where they are involved in ACh-mediated inhibition of further ACh release (opposite of nAChR)
97
N(m)
skeletal muscle nAChR contains four distinct subunits: 2alpha, beta, delta, and epsilon in the adult, and epsilon is replaced by gamma in newborns arranged in a pentameric structure around a central pore
98
N(N)
peripheral neuronal nAChR exist at autonomic ganglia and adrenal medulla as pentamers made up of alpha and beta subunits
99
Central neuronal nAChR
*as opposed to N(N) and N(m) least understood subtype of nAChRs Pentameric receptors can be heteromeric or homomeric in organization at both pre and post synaptic locations
100
Pre-synaptic nAChR
stimulates more ACh vesicles to be mobilized for release

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