Pharmacology of NMJ Flashcards
What is the ACh vesicular transporter?
ATP-dependent transporter that moves ACh into storage vesicles after synthesis
Where are mAChR?
Smooth muscle
cardiac muscle
What do curare alkaloids (tubocurarine) cause symptom-wise?
flaccid paralysis of skeletal muscles
used during anesthesia
How are the affects of tubocurarine reversed?
by increasing ACh in NMJ = AChE inhibitor
Would a AChE inhibitor used to treat myasthenia gravis be charged or uncharged?
charged - want to only affect skeletal muscle NMJs
if you use uncharged molecules, could affect CNS - not what you want here
What are the 2 agents that affect depolarization?
curare alkaloids (d-tubocurarine) = antagonist succinylcholine = agonist
How do curare alkaloids work?
What is the prototype?
antagonists for nicotinic receptor: compete w/ ACh –> decrease size of the EPP = no synaptic transmission
prototype = d-tubocurarine
How is ACh removed from IMJ?
Acetylcholinesterase (AChE) cleaves ACh into choline and acetate
Choline recycled back into motorneuron
What are symptoms of tetanus?
spastic paralysis, lockjaw
autonomic overactivity
rigid muscles
What does a muscarinic receptor cause in smooth muscle?
contraction
How does succinylcholine work?
agonist of nicotinic receptor:
binds to receptor and causes continued depolarization –> eventual paralysis
Why are nAChRs selective for the ions they allow through?
negatively charged AAs line pore –> affinity for positively charged ions = mainly Na+
What are the 2 agents that affect veisicular ACh release/
Botulinum toxin
tetanus toxin
What receptor is a ligand-gated ion channel?
nicotinic AChRs
Where is tetanus found and how does it work?
found in soil
blocks fusion of synaptic vesicles by targeting synaptobrevin (a SNARE protein)
after binding to presynaptic memrane, it is internalized and transported retroaxonally to spinal cord
What is myasthenia Gravis?
What are hallmark symptoms?
Autoimmune disorder where Ab attack nicotinic receptors
ptosis (droopy eyelids), fatigue that worsens throughout day and w/ activity
neural conduction, sensory, and autonomic responses are normal
Once Ca enters the pre-synaptic neuron upon depolarization, what proteins help vesicle-PM fusion?
What type of proteins are they?
VAMP and SNAPs
Plasma membrane proteins
How does dantrolene work and what are its clinical uses?
inhibits ryanodine receptors in SR of muscle cells –> no calcium release –> no muscle contraction
treats malignant hyperthermia, spasticity assoc w/ upper motor neuron disorders
Where are nicotinic AChR?
What do they cause in the post-synaptic tissue?
skeletal muscle, peripheral neuronal, central neuronal
contraction
When is succinylcholine used and what are its hallmark effects?
used as an induction agent for anesthesia
fast and short acting
causes muscle fasciculations and then paralysis
What are agonists of skeletal muscle nicotinic receptors?
ACh
nicotine
Succinylcholine
What is the mechanism of ACh synthesis?
Choline enters cell via choline transporter –> Choline acetyltransferase (ChAT) combines choline w/ Acetyl CoA –> ACh
How do you treat Myasthenia Gravis?
use AChE inhibitor –> more ACh at NMJ can restore some normal function
What is the antagonist of Peripheral neronal and central neronal nicotinic receptors?
mecamylamine
What is tetrodoxin and how does it work?
puffer fish poison
Inhibits voltage-gated Na+ channels on neuron –> no axonal conduction
What are antagonists of skeletal muscle nicotinic receptors?
d-tubocurarine
atracurium
vecuronium
pancuronium
What does a muscarinic receptor cause in cardiac muscle?
decreased:
HR, conduction velocity, contraction
How does the botulinum toxin work?
cleaves components of SNARE complex –> ACh cant be exocytosed –> no muscle contraction
About how many vesicles rupture per AP?
125
What disease causes reduced cerebral production of ChAT? What would this in turn cause?
Alzheimers
less production of Acetylcholine
How do local anaesthetics work?
inhibit voltage-gated Na channels on neuron –> no AP
What are symptoms of botulism?
acute onset of bilateral cranial neuropathis w/ symmetric descending weakness
no sensory deficits except blurred vision
nausea, vomiting, abdominal pain, diarrhea, dry mouth
When is an AChE inhibitor used?
to increase concentration of ACh at NMJ
treats: dementia assoc w/ alzheimer or parkinson’s; myasthenia gravis, nerve gas and pesticide exposure, reversal of anesthesia
