3 NMJ Flashcards
motor unit consists of
the motor nerve and all the muscle fibres innervated by that nerve
all the muscle fibres within a motor unit contract together when the motor nerve fires
size of motor unit varies
depends on function of the muscle innervated
individual innervation of fibre
each individual muscle fibre is separately innervated by the nerve (no gap junctions between fibres) so has t have direct contact via NMR
more fibres innervated = stronger contraction
1:1 transmission means
chemical transmission which is designed so that every presynaptic action potential results in a postsynaptic one
time delay of transmission across NMJ
0.5-1ms
NMJ easily affected by
drugs
NMJ location
synapse between motor neuron and skeletal muscle fibres = bridges gap as they do not touch
how CNS links to NMJ
Motor nerve cell bodies sited in the ventral horn of the spinal cord send out axons via ventral roots to innervate the appropriate muscles
These axons are myelinated as they pass through the CNS and into the peripheral nerves but divide to supply thin unmyelinated fibres, which can each innervate several individual muscle fibre cells
nAChR’s =
nicotinic acetylcholine receptor
nicotinic vs muscarinic
nicotinic = ionotropic receptor
muscarinic = metabotropic receptor (GPCR)
cholinergic (receptor)
responds to ACh binding
2 types:
- nicotinic = nAChR
- muscarinic = mAChR
basal lamina
support within the synaptic cleft = AChE is attached to
structure of nAChR’s
- formed from 5 subunits
- each subunit formed from 4 transmembrane segments
nAChR’s have different subunit types
so different types of nAChR depending on composition = affects pharmacological profile
subunits in nAChR’s
5 subunits total = heteromeric receptor
2 alpha
1 beta
1 gamma
1 delta
(2) alpha subunits in nAChR’s
= have ACh binding sites – 2 molecules of ACh must bind to receptor before receptor is activated (one on each alpha subunit)
MEPPs
Miniature End Plate Potentials
1 quantum
= contents of 1 synaptic vesicle (5000 molecules of ACh)
what is an MEPP
ACh released as a random event (i.e. no action potential or calcium influx necessary) – smallest measurable event in transmission = don’t get parts of quanta released, either 1 quantum or multiples of 1
many MEPPs together
= when action potential causes release of many vesicles, forms EPP – generates action potential
inactivation of ACh
ACh hydrolysed by AchE
products of hydrolysis of ACh
ACh -> acetate + choline
choline is reabsorbed by presynaptic cell
acetyl CoA + choline -> acetylcholine + CoA
(acetate + CoA -> acetyl CoA)
docking of vesicles containing ACh
v-snare protein on Vesicle binds with t-snare on presynaptic membrane
get ACh into vesicle
co-transport H+ out, ACh in
agonist
binds to the receptor and produces an effect within the cell
antagonist
binds to receptor and blocks response
nAChR antagonist = non-depolarising
tubocurarine
drugs used at NMJ:
blocking agents can be depolarising or non-depolarising
depolarising
non-depolarising = no APs generated
action of tubocurarine
competes with Ach for nicotinic receptor binding sites
effect of tubocurarine at NMJ
muscle paralysis occurs gradually
therapeutic use = surgery as an anaesthetic
onset =5 mins
duration 30 mins
adverse effects of tubocurarine
hypotension (increases histamine release, a vasodilator)
bronchospasm
reversal of tubocurarine
increase ACh conc in synaptic cleft
= AChE inhibitors
nAChR agonist = persistent depolarising
succinylcholine
action of succinylcholine
persistent depolarization of the neuromuscular junction = motor end plate
works similar to ACh but is longer acting (as is broken down less rapidly)
effect of succinylcholine
phase I:
= membrane depolarized causing brief period of muscle fasciculation (twitching)
phase II:
(desensitizing phase)
= end-plate eventually repolarizes, but because succinycholine is not metabolized like ACh it continues to occupy the AChRs to “desensitize” the end-plate
The muscle is no longer responsive to ACh released by the motoneurons. At this point, full neuromuscular block has been achieved.
=Flaccid paralysis
adverse effects of succinylcholine
when administrated with halothane genetically susceptible people experience malignant hyperthermia
reversal of succinylcholine
hydrolysed by esterases
therapeutic use of succinylcholine
surgery continuous IV
short acting
cholinesterase inhibitor examples (2)
Neostigmine, edrophonium
mechanism of cholinesterases
inhibits AChE
therapeutic uses of cholinesterase inhibitors
Antidote for non depolarising blockers such as Tubocurarine
Treatment for myasthenia gravis (neostigmine)
Diagnosis of myasthenia gravis (edrophonium)
adverse effects of AChE inhibitors
Abdominal cramping, diarrhoea, salivation, incontinence, actions on paraSymp NS, hypotension, bradycardia, GI tract hypermotility, bronchoconstriction
sarin weapon action
“nerve gas”
AChE inhibitor
- muscles can contract in powerful convulsive reactions
- nose and eyes can water severely and drooling
- nausea and vomiting
- constriction of the pupils to pinpoints
- loss of control of bowel and bladder can follow
- chest pain, shortness of breath, collapse, seizures
- > death is the end result
toxin effects at NMJ = Tetanus and botulinum
prevent vesicles binding to presynaptic membrane
action of botulinum toxin
disease = botulism, caused by bacteria
cleaves SNARE proteins = involved with fusing synaptic vesicles to the plasma membrane
= inhibits the release of acetylcholine at NMJ
-> flaccid paralysis
