Pharmacology of the Neuromuscular Junction Flashcards
ACh Synthesis: choline transporter
Membrane channel that transports the choline into the cell
ACh Synthesis: Choline acetyltransferase and impact on patients with alzheimers
Enzyme that combine acetyly Coenzyme A and choline to form ACh
Patients that have Alzheimers disease have reduced Cerebral production of ChAT (choline acetyltransferase
ACh Storage: ACh vesicular transporter
ATP dependant transporter that shuttles ACh into the storage vesicles after the production of ACh
a motor nerve terminal may contain 300k of these
ACh Release: Voltage gated Ca2+ channels
these open upon depolarization of the cell that allow the Ca2+ to enter the cell and promote vesicle membrane fusion
ACh Release: VAMP and SNAP
vesicular and plasma membrane proteins that initiate vesicle plasma membrane fusion and release of the ACh
about 125 of these vesicles rupture per action potential
ACh Destruction: Acetylcholinesterase (AChE)
enzyme that cleaves the ACh into choline and acetate
choline will then recycle back to the motorneuron via the choline transporter
Nicotinic Acetylcholine receptors:
activated by ACh and nicotine
ligand gated ion channel (Na+)
Pre- and post junctional
NMJ: Na+ increases causes muscle action potential
Found at Skeletal muscle
ionotropic- ligand gated ion channels that allow for ions to pass through the channel pore when activated
Muscarinic Acetycholine receptors
Activiated by ACh and muscarine
G protein coupled receptor
Pre and post junctional
Not located at skeletal NMJ
at smooth muscle and cardiac muscle
decreases HR and contraction
metabotropic- activation leads to intracellular events that trigger secondary messengers
How are the Ligand Gated Ion channels selective?
Ions are selected based on the charge of the amion acids lining the pore of the channel
Negative charged amino acids line the pore of channels that pass positively charged ions
Positive charged amino acids line the pore of channels that pass negatively charged ions through it
what line the LGIC in nAChRs
Aspartic acid and glutamic acid line pore (negative charge)
allow for the channel to be selective to Na+, Ca2+, and K+
nAChRs Skeletal muscle receptor Nm characteristics: Synaptic location, membrane response, Molecular response
location: Skeletal Neuromuscular junction
Membrane response: Excitatory, contraction
Molecular response: Increased cation permeability (Na+, K+)
nAChRs Skeletal muscle receptor (Nm) characteristics: Agonists, and antagonists
Agonists: ACh, Nicotine, succinylcholine
Antagonists: d-tubocurarine
Atracurium
Vecuronium
Pancuronium
nAChRs Peripheral Neuron receptor (Nn) Characteristics: Synaptic location, membrane response, Molecular response
Synaptic location: Autonomic ganglia, adrenal medulla
Membrane response: Excitatory, depolarization
Molecular response: Increased permeabillity (Na+, K+)
nAChRs Peripheral Neuron receptor (Nn) characteristics: Agonists, Antagonists
Agonists: ACh, Nicotine
Antagonists: Mecamylamine
nAChRs Central Neuron receptor Characteristics: Agonists, antagonists
Agonists:ACh, and Nicotine
Antagonists: Mecamylamine
nAChRs Central Neuron characteristics: Synaptic location, membrane response, Molecular response
Synaptic Location: CNS
Membrane response: Excitatory pre-junctional control of ACh release
Molecular response: Increased cation permeabillity (Na+, K+, and Ca2+)
9 Events that occur at the NMJ
1) an Action potential in the motor neuron is propagated to the terminal button
2) THe presence of an AP triggers the opening of the voltage-gated Ca2+ channels
3) Ca2+ triggers the release of ACh from vesicles
4) ACh diffuses across the synaptic cleft and activates the nAChRs
5) nAChRs open leading to a relatively large influx of Na+ compared to a smaller efflux of K+
6) Local current flows between the depolarized end plate and adjacent membrane
7) local current flow opens voltage gated Na+ channels
8) Influx of Na+ initiates an AP, which propagates throughout the muscle fiber
9) ACh is destroyed by the AChE terminating the muscles cells response
Tetrodoxin
Affects Nerve AP
Puffer fish poison, not used clinically,
inhibition of voltage gated Na+ channels blocks axonal conduction
Symptoms: weakness, dizziness, paresthesias of face and exftremities, loss of reflexes, hypotension, generalized paralysis, death can occur due to respiratory failure and hypotension
Local Anesthetics:
Affects Nerve AP
Inhibition of voltage gated Na+ channels inhibition axonal conduction
utilized for pain control during a variety of clinical procedures
Lidocane, bupivacaine, procaine
Botulinum Toxin
Affects Vesicular Release
Botulism caused by clostridium botulinum, gram positive spore forming anerobic bacteria
found on vegetables, fruits, seafood, and exists in soil and marine sediment
MOA: cleaves components of the core SNARE complex involved in exocytosis preventing the release of ACh
classically described as acute onset of bilateral craniel neuropathises leading to symmetric descending weakness
blurred vision,
foodborne lead to nausea, vomiting, abdominal pain, diarrhea, and dry mouth
used for appearance and chronic migraine headache
Tetanus Toxin
Affects the vesicular ACh release
Nervous system disorder characterized by muscle spasms that are caused by the toxin producing anaerobe Clostridium Tetani which is found in the soil
MOA: Blocks fusion of the synaptic vesicles by targeting synaptobrevin
the toxin binds to the presynaptic membrane and then is internalized and transported to the spinal cord
it then acts on the spinal inhibitory interneurons blocking the release of inhibitory neurotransmitters that normally serve to relax contracted muscles
spastic paralysis with things like lockjaw
autonomic overactivity, (restlessness, sweating, tachycardia) stiff neck, board like abdomen
How do agonists and antagonists of the nAChR prevent synaptic transmission
Agonists: activate the receptor to signal as a direct result of binding it
antagonists: bind to receptors but do not activate generation of a signal
Curare Alkolids
Affects Depolarization
d-tubocurarine is the prototype
Competes with the ACh for the nAChR on the motor end plate, it decreases the size of the EPP (nondepolarizing competitive nAChR antagonists
leads to flaccid paralysis of the skeletal muscle
makes the skeletal muscle relax
can be reversed by increasing the ACh in the NMJ (AChE inhibitor)
Succinylcholine
Affects depolarization
Depolarizing neuromuscular blocker that binds to skeletal muscle nAChRs and initially causes a depolarization (acts as an agonist), but then continued depolarization leads to receptor blockade and paralysis
used as an induction agent for anesthesia
paralysis reversed by termination of succinylcholines effects
Cholinesterase Inhibitor
Inhibits AChE
bind to AChE and vlocks its enzymatic activity
increases the concentration of ACh at the NMJ
used for demential associated with alzheimers or Parkinson, myasthenia gravis, nerve gasm and organophosphate pesticide exposure, reversal of neuromuscular blockade during anesthesia
Dantrolene
Affects muscle contraction
inhibits the ryanodine receptors in the sarcoplasmic reticulum and blocks the release of Ca2+
used for malignant hyperthemia, spasticity associated with upper motor neuron disorders
