Pharmacology - NMJ Flashcards
Steps involved in NMJ neurotransmission
- Axonal conduction
- Junctions transmission
- ACH signaling
- Muscle contraction
Junctions transmission
- ACH synthesis
- ACH storage
- ACH release
- ACH destruction
Membrane channel that transports choline into cell
Choline transporter
Enzyme that combine acetyl coenzyme A (AcCoA) and choline to form ACH
Choline acetyltransferase (ChAT)
Choline transporter inhibitor
Hemicholinium
Opens upon depolarization and allows Ca2+ to enter the cell
Voltage-gated Ca2+ channels
What does release of Ca2+ via voltage-gated Ca2+ channels promote?
Vesicle membrane fusion
Vesicular and plasma membrane proteins that initiate vesicle-plasma membrane fusion and release of ACh
VAMP and SNAPs
What does acetylcholinesterase (AChE) cleave acetylcholine into?
Choline and acetate
What happens to the choline produced by breakdown of ACh?
Recycled back into motor neuron via choline transporter
What process occurs are the nerve terminal to replenish number of available vesicles?
Endocytosis
2 subsets of acetylcholine receptors
- nicotonic acetylcholine receptors (nAChRs)
- muscarinic (mChRs)
- activated by ACh and nicotine
- ligand-gated ion channel (Na+)
- pre and post-junctions
- at NMJ: Na+ increase causes muscle AP
NAChRs
- activated by ACh and muscadine
- GPCR
- pre and post-junctions
- NOT located at skeletal NMJ
MAChR
Where are mAChRs found?
- smooth muscle
- cardiac muscle
Function of nAChR and mAChr in skeletal muscle and smooth muscle (respectively)
Contraction
Function of mAChR in cardiac muscle
Decreased HR, conduction velocity, contraction
Number of mAChR subtypes in mammals
5 (M1-M5)
Metabotropic
Activation leads to series of intracellular events triggered by second messengers
Ionotropic
Ligand-gated ion channels allow ions to pass through channel pore when activated
Describe selectivity of ions
Based on charge of amino acid
Ex: negative charge within pore of nAChR = allows positive ions to pass
Molecular response of all types of nAChRs
Increased cation permeability (Na+ and K+; Ca2+ in CNS)
Agonists of skeletal muscle (Nm)
ACh
Nicotine
Succinylcholine
Antagonists of skeletal muscle (Nm)
- d-tubocurarine
- atracurium
- vecuronium
- pancuronium
Antagonists of peripheral neuronal (Na) and central neuronal receptors
Mecamylamine
Synaptic location for peripheral neuronal (Nn) vs. central neuronal
- peripheral neuronal: autonomic ganglia & adrenal medulla
- central neuronal: CNS
Events at the NMJ
- AP propagated to terminal button
- AP triggers opening of voltage-gated Ca2+ channels
- Ca2+ triggers release of ACh from vesicles
- ACh diffuses across synaptic cleft and activates nAChRs
- NAChRs open > large include of Na+ compared to small effluent K+
- Local current flows b/w de polarized end plate and adjacent membrane
- Local flow opens voltage-gated Na+ channels
- Influx of Na+ initiates an AP which propagates throughout muscle fiber
- ACh is destroyed by ACHE, terminated cells response
Tetrodotoxin, batrachotoxin, local anesthetics
Block nerve AP
Hemicholinium, botulinum toxin, procaine, Mg2+, 4-aminopyridine, lack of Ca2+
Block vesicular acetylcholine release
Excess of Ca2+
Promotes vesicular acetylcholine release
Curare alkaloids and snake alpha-toxins
Block depolarization (EPP) (increased permeability to Na+ and K+)
Succinylcholine and decamethonium
Depolarization and phase II block
Cholinesterase inhibitors
Block hydrolysis of acetylcholine by cholinesterase
Ca2+ and veratridine
Enhance muscle AP
Quinine and tetrodotoxin
Block muscle AP
Metabolic poisons, lack of Ca2+, procaine, dantrolene
Block muscle contraction
- puffer fish poison
- inhibition of voltage-gated Na+ channels block axonal conduction
- weakness, dizziness, paresthesia of face and extremities, loss of reflexes, hypotension, general paralysis, death from respiratory failure and hypotension
Tetrodotoxin
- inhibition of voltage-gated Na+ channels inhibition axonal conduction
- used for pain control during clinical procedures
- ex: lidocaine, bupivicaine, procaine
Local anesthetics
- cleaves components of core SNARE complex involved in exocytosis, preventing release of ACh
- caused by Clostridium botulinum (heterogenous group of gram-positive, rod-shaped, sport-forming, obligate anaerobic bacteria; found on vegetabless, fruits, seafood, etc.)
- classically described as cute onset of bilateral cranial neuropathies associated with symmetric descending weakness
- used with temporary improvement in appearance of lines/wrinkles of face, prophylaxis of chronic migraine headache
Botulinum toxin
Nervous system disorder characterized by muscle spasms caused by Clostridium tetani (toxin-producing anaerobes) found in soil
Tetanus
- block fusion of synaptic vesicles by targeting synaptobrevin
- after blinding to presynaptic membrane of NMJ, tetanus toxin is internalized and transported retroaxonally to SC
- spastic paralysis caused by toxins actions on spinal inhibitory interneurons, blocking release of inhibitory NT that serve to relax contracted muscle by inhibiting excitatory motor neurons
Tetanus toxin
Spastic paralysis with symptoms that include trismus, autonomic overactivity, stiff neck, board-like rigid abdomen, opisthotonos, dysphasia
Symptoms of tetanus
Activate receptor to signal as a direct result of binding to it
Agonist
Bind to receptors but do not activate generation of signal
Antagonists
- Competes with ACh for the nAChR on the motor end plate > decrease size of EPP
- inhibits ACh binding to nAChR > flaccid paralysis of skeletal muscle
- used during anesthesia to relax skeletal muscle
- paralysis reversed by increasing ACh in the NMJ
Curare alkaloids (d-tubocurarine)
- depolarizing neuromuscular blocker that binds to skeletal muscle nAChRs and causes depolarization > continued depolarization leads to receptor blockade and paralysis
- used as induction agent for anesthesia
- paralysis reversed by termination of succinylcholine’s effects
Succinylcholine
- bind to AChE and block enzymatic activity
- increase concentration of ACh at the NMJ
- clinical uses: dementia (Alzheimer’s or Parkinson’s), myasthenia Travis, nerve gas and organophosphate pesticide exposure, reversal of neuromuscular blockade during anesthesia
Cholinesterase inhibitors
- inhibit RyR in the SR and blocks release of Ca2+
- clinical use: malignant hyperthermia, spasticity associated with upper motor neuron disorders
Dantrolene
blocks the ACh vesicular transporter
Vesamicol
