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

Dr. Kruse's Pharmocology of NM junction Flashcards

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
Q

Which of the two receptors is a ligand gated channel and which is a 7 transmembrane domain channel?

A

Nicotinic is a voltage gated channel

Muscarinic uses G coupled proteins

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26
Q

mAChRs are

A

GPCRs

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27
Q

How many subtypes of GPCRs are there in mammals?

A

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

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28
Q

nAChRs are what? what do they do? what is their speed?

A

ligand gated ion channels

allow ions to pass through the channel pore when activated (ionotropic)

fastest synaptic event in the nervous system (miliseconds)

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29
Q

how many subunits does a the nAChR have?

A

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

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30
Q

Ionotropic versus metabotropic channels

A

Ionotropic: nAChRs
metabotropic: mAChRs

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31
Q

What kind of amino acids do we expect to line the LGIC?

A

aspartic acid and glutamic acid (negatively charged)

channels selective to Na, Ca, and K

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32
Q

nAChRs antagonists

A

Atracurium
Vecuronium
d-tubocuranine
Pancuronium

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33
Q

What happens when an antagonist interacts with the nAChRs

A

a signal cant be sent, so its an anesthetic

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34
Q

Nm vs Nn

A

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

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35
Q

Nn

A

include a and b combinations or all a subunit
found in the CNS, autonomic ganglia, adrenal medulla
receptors are pre-posjunctional

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36
Q

Nm

A

nclude a, b, d, e and g subunits

found ONLY at skeletal muscle motor end plates
receptors are pre-post ganglionic

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37
Q

NAChR postjunctional activity

A

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

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38
Q

End plate depolarization

A

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

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39
Q

does the motor end plate fire an action potential?

A

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

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40
Q

Na/K influx/efflux

A

Na diffuses inwards in large concentrations while K diffuses outwards in smaller concentrations

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41
Q

Activation of what receptor will inhibit further ACh release?

A

mAChR

42
Q

Tetrodotoxin ‘

A

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
Q

local anesthetics

A

MOA inhibition of voltage gated Na channels–> inhibition of action potential

utilized for pain control

lidocain
bupivacaine
procaine

44
Q

Batrachotoxin

A

poison dart frog:
causes an increase in permeability of Na channels and induces persistent depolarization

very toxic

45
Q

Botulinum toxin

A

clostridium botulinum
a group of heterogenous, gram + rod shaped, spor forming obligate anaerobic bacteria

8 types cause human disease ABE, rarely FGH

46
Q

Botulinum toxin action

A

cleaves SNARE complex involved in exocytosis prevents release of ACh

47
Q

How is botulism classified?

A

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
Q

Synaptobrevin is the target of

A

tetanus and Botulinum BDFG

49
Q

SNAP-25 is the target of

A

Botulinum AVE

50
Q

Syntaxin is the target of

A

Botulinum C1

51
Q

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?

A

1) Tetrodoxin
2) Botulinum toxin
3) Tetanus

52
Q

Tetanus act specifically on the

A

interneurons of the spinal cord: blocks release of inhibitory NTs

53
Q

how does tetanus present?

A

spasms/muscle spasms

54
Q

Which symptom corresponds to which toxin?

1) Diarrhea, nausea, vomiting, abdominal pain
2) Respiration failure
3) spastics

A
  1. botulism
  2. tetrodoxin
  3. tetanus
55
Q

NAChR agonists and antagonists

A

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
Q

Curare alkaloids

A

competes with Ach for the nAChR receptors on the motor end plate

57
Q

Curare binding to the nAChR does what

A

inhibition: flaccid paralysis of skeletal muscle

58
Q

when are curares used?

A

to inhibit nAChR receptors to induce flaccid paralysis

used during anesthesia to relax skeletal muscle

59
Q

paralysis by curares can be reversed how?

A

by increasing ACh in NMJ

60
Q

Succinylcholine

A

depolarizing neuromuscular blocker that binds to nAChR on skeletal muscle and causes depolarization

continued depolarization leads to receptor blockage and paralysis

61
Q

What is succinycholine used for?

A

it induces anesthesia

62
Q

How is succinylcholine’s paralytic effects reversed?

A

time. gotta wait it out.

63
Q

Curate is a ______ blocker; succinylcholine is a ______ blocker

A

non-depolarizing; depolarizing

depolarizing physically blocks the receptors, nondepolarizing prevents them from opening

64
Q

Cholinesterase inhibitors

A

bind to AChE and block enzymatic activity

AChE breaks ACh down in the NM cleft, so inhibition would increase ACh

65
Q

Clinical use of cholinesterase inhibitor

A

include dementia associated with alzheimer or parkinson disease, myasthenia gravis, nerve gas,

reversal of neuromuscular blockade during anesthesia

66
Q

Agents that effect the muscle AP versus muscle contraction (two in mind)

A

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
Q

Dantrolene

A

inhibits ryanodine receptors in the SR: blocks Ca release

used to fight malignant hyperthermia and spasticity associated with upper motor neuron disorders

68
Q

what clinical use does dantrolene have?

A

fights against malignant hyperthermia and spasticity

69
Q

Vesicles in neurons come from where?

A

motor neuron cell body in the CN

70
Q

Vesicles for ACh: how do they travel from the motor neuron to the axon terminal?

A

they travel empty

71
Q

Vesicles for peptide NTs: how do they travel from the motor neuron to the axon terminal?

A

they travel carrying their full cargo, already synthesized

72
Q

Agents that affect nerve action potentials =

A

tetrodotoxin

local anesthetics

73
Q

Agens that affect the vesicular acetylcholine release

A

botulinum toxin
tetanus toxin
Hemicholinium

74
Q

Agents that affect depolarization

A

neuromuscular blocking drugs: Curare alkaloids and Succincylcholine

75
Q

Agents that inhibit acetycholinesterase

A

AChE inhibitors (duh)

76
Q

Agents that affect the muscle action potential

A

Veratridine (stimulates Na passage into cells and leads to increased nerve exctiability)
Tetrodotoxin

77
Q

Agents that affect muscle contraction

A

Dantrolene

78
Q

Choline enters the neuron how?

A

through a symporter with Na

79
Q

CHaT

A

Choline acetyltransferase

combines acetyl Co-A and choline together to make ACh, an it is immediately put into vesicles

80
Q

How would inhibiting CHaT be helpful?

A

it wouldn’t be because choline entering the cell is the rate limiting step

81
Q

Vesicle membrane fusion: Snares and Vamps

A

SNAREs primary role is mediating vesicle fusion

82
Q

v-SNARE

A

synaptobrevin

83
Q

t-SNARE

A

syntaxin

84
Q

SNAP-25 does what?

A

it interacts with synaptobrevin and syntaxin to form the core SNARE complex that brings the vesicle and presynaptic membranes into close contact

85
Q

synaptotagmin

A

the protein that is effected by Ca2+ rushing into the neuron. synaptotagmin triggers the vesicle fusion and exocytosis

86
Q

alpha-SNAP and ATPase NSF

A

in synaptic cleft: they dissasemble SNAREs, allowing recycling of vesicle and SNARE proteins

87
Q

What proteins make up the protein complex causing ACh containing vesicles to come near the membrane?

A

v-SNARE (synaptobrevin) + t-SNARE (syntaxin) + SNAP-25

88
Q

What protein triggers the actual vesicle fusion?

A

synaptotagmin

89
Q

What proteins breakdown the SNARE complex?

A

alpha-SNAP and the ATPase NSF.

90
Q

What are the energy requirements for membrane disassembly?

A

the alpha-SNAP and NSF complex require one ATP

91
Q

mAChRs: how many subtypes exist?

A

5

92
Q

mAChRs: predominant type found in muscle and cardiac tissue

A

M2 & M3 = smooth muscle

M2 = cardiac muscle

93
Q

metabotropic

A

mAChR, GCPR :activation leads to a series of intracellular events triggered by secondary messengers

94
Q

mAChR agonist

A

ACh or muscarine

95
Q

how do agonist bind?

A

they bind to the long extracellular amino-terminus and activate intracellular g proteins

96
Q

mAChRs are located…

A

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
Q

N(m)

A

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
Q

N(N)

A

peripheral neuronal nAChR

exist at autonomic ganglia and adrenal medulla as pentamers made up of alpha and beta subunits

99
Q

Central neuronal nAChR

A

*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
Q

Pre-synaptic nAChR

A

stimulates more ACh vesicles to be mobilized for release

MSKI Final Exam material (15 decks)

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