Pharmacology of the Neuromuscular Junction Flashcards
What are the four steps in NMJ neurotrasmission?
1) axonal conduction
2) Junctional Transmission (4 steps)
3) ACh signaling
4) Muscle contraction
What are the four steps in junctional transmission?
- ACh synthesis (NT)
- ACh storage
- ACh release
- ACh destruction
What are the two main steps in ACh (acetylcholine) synthesis?
- Choline is transported into the cell by a choline transporter
- Choline acetyltransferase (ChAT) combines acetyl coenzyme A (AcCoA) and choline to form ACh
How is ACh stored in a pre synaptic neuron and how many are in each synaptic vessle?
Once ACh is made, it is transporter into the storage vessicle by using ATP dependent ACh vesicular transporter. Approx. 1K-50K ACh per vessicle
(motor nerve terminals contain 300K)
What are the main factors to the release of ACh? (2)
- voltage gated Ca2+ channels open upon depolarization and Ca enters, promoting vesicle membrane fusion
- VAMPS/SNAPS (vesicular plasma membrane proteins) initiate vesicle-plasma membrane fusion and release of ACh (125 vesicles per AP)
What are the main steps in ACh destruction after it elicits a post synaptic response?
Acetylcholinesterase (AChE) will cleave ACh into choline and acetate.
Choline is reuptaked into cells via choline transporter
What is unique to nAChRs to which ACh can bind? (4)
Activated by ACh/Nicotine, ligand gated ion channel (Na+), pre and post junctional, NML: Na+ increase causes AP
What is unique to mAChRs to which Ach can bind? (4)
activated by ACh/Muscarine, GPCR, Pre/postjunctional, not located at skeletal NMJ
What receptor for ACh when activated leads to a series of intracellular events triggered by secondary messengers (metabotropic), whose cellular effects are measured in seconds?
mAChRs
What receptor for ACh actives ligand gated ion channels which allow ions to pass through the channel pore when activated (ionotropic), whose cellular effects are measured in miliseconds?
nAChRs
The ions that go through a ligand gated ion are selected based on the charge of the amino acids lining the channel, what amino acids line the nAchRs and what do they have selectivity to?
Aspartic acid and glutamic acid line the pore (negative charges) meaning it needs positive charged molecules such as Na+, Ca+ and K+ to go through (more Na+ in skeletal muscle)
Tertrodotoxin (What is it, MOA, Symptoms)?
Puffer fish poison
Inhibits voltage-gated Na+ channels, blocks axonal conduction (affects AP)
Weakness, Dizziness, Parethesias of face/extremities
Local anesthetics (MOA, derivatives)?
Inhibits voltage gated Na+ channels, blocking axonal conduction (affects AP)
Used for pain control: lidocaine, bupivacaine, procaine
Botulinum Toxin (What is it, MOA, Symptoms)?
gram-pos, rod shaped anaerobic bacteria in fruits/vegs/soil
cleaves core SNARE complex involved in exocytosis, preventing release of ACh from vesicle
clinically used for lines and wrinkles of the face/ prophylaxis of chronic migraine headache
Tetanus Toxin (What is it, MOA, Symptoms)?
Nervous system disorder characterized by muscle spasms, caused by toxin producing clostridium tetani in soil
blocks flusion of synaptic vesicles/release of ACh by targeting synaptobrevin, once binds to NMJ will go to spinal cord and inhibit release of inhibitory neurotramsitters that normally serve to relax contracted muscle by inhibiting excitatory motor neurons
Spastic paralysis, jawlock, restlesness/sweating, stiff neck, rigid abdomen, dysphagia
Agonist vs. antagonist in neuromuscular blocking of nAChRs?
Agonist: activate receptor to signal d/t binding to it
Antagonist: binds to receptor but do not activate signal
Curare alkaloids-Antagonist (What is it, MOA, Symptoms)?
d-tubocurarine (nondepolarizing blocker)
competes with ACh for the nAChR on motor end plate, decreasing size of EPP - inhibition of ACh binding to the nAChR (no depolarization!) leads to flaccid paralysis of muscles
used in anesthesia to relax muscle, reversed by increasing ACh in the NMJ - AChE inhibitor
Succinylcholine- agonist (What is it, MOA, Symptoms)?
depolarizing nueromuscular blocker that binds to skeletal muscle nAChRs and initially cause depolarization, and continued depolarization leads to receptor blockade and paralysis because does not close
used as induction agent for anesthesia, paralysis reversed by time (metabolism metabolizes it)
Cholinesterase inhibitors (What is it, MOA, Symptoms)?
Bind to AChE and block enzymatic activity, increasing the concenctration of ACh at the NMJ
Used for dementia associated with alzheimer/parkinson, myasthenia gravis, nerve gas
Dantrolene (What is it, MOA, Symptoms)?
Inhibits ryanodine receptors (end feet) in sarcoplasmic reticulu, and blocks release of Ca2+ (blocking muscle contraction)
Used in malignant hyperthermia, spasticity associated with upper motor neuron disorders
Agents that affect the nerve action potential? (2)
Tetrodotoxin
Local Anesthetics
Agens that affect vesicular acetylcholine release? (2)
Botulinum toxin
Tetanus toxin
Agents that affect depolarization? (2) (Neuromuscular blocking drugs)
Curare alkaloids (d-tubocurarine) Succinylcholine
Agent that inhibit acetylcholinesterase?
Acetylcholinesterase inhibitors
Agent that affect the muscle action potential?
Tetrodotoxin
Agent that affect muscle contraction (block ryanodine the end feet between t tubules SR)?
Dantrolene
