The NMJ From a Pharmacological Perspective Flashcards
what to know?
put out notes packet** read it
junctional transmission
cholinergic > bc ACh is neurotransmitter
4 important steps in junctional transmission
synthesis of ACh
storage
release
degradation
*every neurotransmitter undergoes this process
4 steps in NMJ neurotransmission?
axonal conduction
junctional transmission
ACh signaling
muscle contraction
when does junctional transmission occur?
when axonal signal reaches terminal
what is activated by ACh?
nAChR
nicotinic acetylcholine receptors
choline transporter
membrane channel transports choline into cell
choline is precursor to ACh
cotransport of Na+ and choline into cell
choline acetyltransferase
ChAT
enzyme that combines acetyl CoA and choline to form ACh
hemicholinium
blocks the choline transporter
**don’t need to know - bc its used in labs, not clinically
patients with alzheimers?
reduced cerebral production of ChAT
-therefore have less formation of ACh
therapy for alzheimers?
to increase ACh levels**
-to make up for loss of low levels
ACh vesicular transporter
shuttles ACh into storage vesicle
**requires ATP
1-5K ACh per vesicle
motor nerve terminal may have over 300K vesicles
voltage-gated Ca2+ channels
open with depolarization and allow Ca2+ entry into cell
promote vesicle membrane fusion
VAMP and SNAPs
vesicular and membrane proteins that initiate vesicle-plasma membrane fusion and release of ACh
how many vesicles fuse per AP?
approximately 125 vesicles
VAMP
vesicle associated membrane protein
SNAP
synaptosome associated proteins
what are components of SNARE complex
VAMP-SNAP
what does botulinum do?
cleaves the SNARE complex so you can’t have vesicle fusion and ACh release
paralyzes muscles**
how long for fusion?
matter of milliseconds
acetylcholinesterase
AChE
enzyme that cleaves ACh
-into acetate and choline
choline transporter
recycles choline back into motor neuron
endocytosis?
occurs at nerve terminal to replenish the number of available vesicles
two sets of receptors for ACh?
nicotinic and muscarinic
nAChR
nicotinic ACh receptor
-also activate by nicotine
ligand gated ion channels (FAST)
sodium to flow into cell
-found pre and post junctionally
causes muscle AP and muscle contraction
mAChR
muscarinic ACh receptor
- also activated by muscarine
- found pre and post junctionally
G-protein coupled receptors (SLOW)
NOT located at skeletal NMJ**
nAChR distribution
skeletal muscle
cause contraction
respond to ACh and nicotine
mAChR distribution
smooth muscle
cause contraction
respond to ACh and muscarine
in cardiac muscle (SA and AV node)
- also on atrium and ventricle
- decreased HR, conduction velocity, contraction
subtypes of mAChR
5 in mammals M1-M5
activation is metabotropic
metabotropic
causes second messenger pathway
ionotropic
nAChR type
- ligand gated ion channel
- allows ions to pass through the channel pore
- in this case, sodium ions**
structure of nAChR
four-five distinct subunits
ACh binding occurs between alpha and adjacent subunit
requires binding of two ACh
subunits different depending on location of receptor
**allows for specific targeting in body of drugs
subtypes of nAChR
skeletal muscle Nm
peripheral neuronal Nn
central neuronal
skeletal muscle Nm subtype
at NMJ
excitatory > contraction
increased cation permeability
antagonists: atracurium vecuronium d-tubocurarine pancuronium
succinyl choline
causes very fast paralysis
even though its an agonist of Nm AChR, its acts as an antagonists
-tires out the receptors
what allows for specificity?
different subunit make up
what passes through nAChR channel?
sodium, potassium, calcium ???
sodium is main mover, which depolarizes and initiates an AP
prejunctional activation?
nAChR help to mobilize more vesicles
-physiological role confusing
on the presynaptic membrane***
mAChR activation results in ACh-mediated inhibition of further ACh release
tetrodotoxin
inhibits voltage gated Na+ channels and prevents axonal conduction in motor neuron
no AP down neuron - paralysis
local anesthetics
inhibits voltage-gated Na+ channels prevent axonal conduction
diaphragm
skeletal muscle
batrachotoxin
causes an increase in permeability of Na+ channels and induces a persistent depolarization
-one of the most potent toxins
botulinum toxin
cleaves components of SNARE
-VAMP and SNAP proteins
stop vesicular fusion
curare alkaloids
non-depolarizing competitive nAChR antagonist
succinylcholine
depolarizing nAChR agonist
only acts on the Nm (skeletal muscle) nAChR
-but acts as antagonist (tires out receptor)
neuromuscular blocking drugs
used for causing muscle paralysis during anesthesia induction
curare and succinylcholine
cholinesterase inhibitor
increase concentration of ACh at NMJ
organophosphates
-activate smooth and skeletal muscles
used in lower concentration therapeutically
therapeutic use of low concentration cholinesterase inhibitor?
dementia, alzheimers, parkinsons, myasthenia gravis, reversal of neuromuscular blockade during anesthesia
myasthenia gravis
decreased in nAChR on surface of cell
-cholinesterase inhibitor will increase ACh to activate the decreased nAChR
tetrodotoxin
also affects sodium channels on muscle cells (inhibits APs)
dantrolene
inhibits ryanodine receptor in SR
- blocks release of Ca2+
- no contraction
clinical use of dantrolene?
malignant hyperthermia, spasticity with upper motor neurons
uptake of choline
rate limiting step
endoytosis of vesicles
facilitated by clathrin
tertodotixin
puffer fish toxin
blocks axonal conduction
-blocks Na+ channels (not used clinically)
local anesthetics
block neuronal conduction
-inhibits Na+ channels
used for pain control during variety of clinical procedures
botulinum
cleaves components of core SNARE complex
-prevents ACh release
treatments: -strabismus -blepharosmam with dystonia -cervical dystonia -wrinkles of face -
curare alkaloids
non-depolarizing competitive nAChR antagonist
during anesthesia to relax skeletal muscle
succinylcholine
neuromuscular blocking drug
binds to nAChR - acts as an agonust
-continued depolarization leads to receptor blockade and paralysis
dantroleine
inhibits ryanodine receptors in SR
-blocks Ca2+ release
malignant hyperthermia
spasticity with upper motor neurons
-spinal cord unjury, stroke, cerebral palsy, MS
