PNP skeletal neuromuscular transmission Flashcards
curare
blocks twitch produced by nicotine and nerve stimulation
spark theory
theory in the early 1900s that thought neuron transmission was done through a direct electrical transfer of information
criteria needed to establish chimical rather than electrical transmission of nerve impulses
synthesis and storage
release
mimic effects of nerve stimulation with exogenous ACh
pharmacological parallels
termination
What experiment showed synthesis and storage of ACh?
acetylcholine was found in motor nerves
made through choline + acetyl CoA
choline acetyltransferase is the enzyme
What experiment showed release of ACh?
ACh could be collected after a nerve stimulation
What experiment showed mimicry?
ACh could be applied without the nerve firing and give rise to a muscle twitch
What are the pharmacological parallels of ACh?
drugs could emulate the stimulation of ACh, and curare could block the effects
What experiments showed termination?
acetylcholinesterases were shown to terminate the action of ACh
ACh -> choline + acetate
end plate
the direct synaptic area of the nerve onto the muscle
will have potentials that are not seen elsewhere in the muscle
end-plate potential
muscle response at the end-plate to a nerve impulse, needs to be sufficiently intense to generate an action potential
miniature end-plate potentials (MEPPs)
action potentials of the end-late that are generated without nerve impulse
due to spontaneous release of vesicles that provide quantums of a few thousand molecules of ACh
quantal hypothesis
the idea that EPPs are integral multiples of MEPPs due to the quantums of ACh that are released
How many quanta of ACh are released into the NMJ during a nerve impulse?
about 100 quanta
active zone
the area of the muscle where the nerve innervates
Describe the structures of the neuromuscular junction.
Describe the molecular process of an action potential.
vesicles are primed or “SNARED”
influx of calcium through a calcium channel due to action potential propagation
fusion of the vesicle with the membrane releases ACh
ACh binds to the post-synaptic ligand-gated sodium channel, which opens
an EPP is generated, if it is large enough it will activate voltage-gated sodium channels to produce a muscle twitch
ACh is degraded by acetylcholinesterases in the junction
hemicholinium
blocks choline uptake, produces smaller MEPPs and smaller EPPs
myasthenia gravis
smaller MEPPs than normal, caused by a reduction in the number of nicotinic ACh receptors
weakness and loss of control of muscles
can have difficulties eating and breathing
TTX
blocks sodium channel responsible for upstroke both pre- and post- synaptically
causes for the decreased influx of calcium ions via calcium channels in response to membrane depolarization
MG2+
aminoglycoside antibiotics
Lambert-Eaton myasthenic syndrome
Mg2+ and calcium channels
along with other impermeant polyvalent cations such as Co2+, Mn2+, Cd2+, La3+ compete with Ca2+ at an external site that that allows Ca2+ entry
reduce neurally-evoked ACh release as well as other neurotransmitters
aminoglycoside antibiotics
reduce evoked ACh release by reducing of Ca2+ entry through Ca2+ channels
Lambert-Eaton Myasthenic Syndrom (LEMS)
disease associated with bronchogenic carcinoma
reflected as reduced number of ACh packets released by nerve impulses due to a reduced number of P/Q type Ca+ channels in the nerve ending
black widow spider venom (BWSV)
active ingredient is alpha-latrotoxin
initially causes a huge asynchronouse barrage of vesicular exocytosis and MEPPs
several hours later, when all ACh release ends, nerve terminals are completely depleted of cholinergic synaptic vesicles
mechanism through increase in calcium channels in the nerve ending, creating an asynchronous rise in cytoplasmic calcium concentrations inr esponse to the venom
botulinum toxin
enormously potent toxin that consists of 7 fractions
each fraction irreversibly cleaves a specific part of one of three SNAREs
prevents the priming of ACh release and thus preventing neurotransmitter release
botulinum toxin type A (BOTOX)
most widespread clinical use - inhibits ACh release by reducing apparent affinity of calcium for the exocytosis process inside the nerve ending
target is a SNARE called SNAP-25, loosely associated with the nerve terminal membrane and linked to the calcium sensor so it can regulate the calcium sensitivity of secretion
clinical uses of BOTOX
blepharospasm and other ocular disorders
hemifacial spasms
laryngeal problems such as stuttering or spasmodic dysphonia
diseases that produce peripheral spasticity in the legs, arms, and hands
spasms associated with repetitive activity such as musician’s cramp and writer’s cramp
autonomic focal hyperhydrosis and urinary incontinence
What toxin produces effects similar to MG?
alpha-bungarotoxin
characteristics of a post-junctional impairment
if EPP amplitudes, MEPP amplitudes, and the response to exogenous ACh are all decreased in parallel regardless of how ACh is applied
lack of responsiveness to ACh is post-junctional
characteristics of a pre-junctional impairment
EPP amplitudes are decreased without a change in MEPP amplitudes (ratio of average EPP to average MEPP potentials is decreased)
decresae in evoked ACh release, very common phenomenon
What are the three SNARE molecules that facilitate vescile fusion to the pre-synaptic membrane?
synaptobrevin
SNAP-25
syntaxin
mechanistic function of Botx/A
cleaves SNAP-25 at amino acid 9 where it interacts with the calcium sensor
Botx/B mechanism
cleaves synaptobrevin
Botx/C mechanism
cleaves syntaxin
synaptogamin
calcium sensor attached to the SNAREs
