Pharmacological view of NMJ Flashcards
cholinergic neuron?
neurotransmitter is ACh
can occur at NMJ and smooth muscle junction
neurons that are responsible for releasing acetylcholine in the brain or periphery
what does junctional transmission involve
Synthesis of acetylcholine (ACh)
Storage of ACh
Release of ACh
Destruction of ACh
almost all steps in this process can be inhibited by pharmacological agents
steps involved in NMJ neurotransmisison
Axonal conduciton
Junctional transmission
ACh signaling
Muscle contraction
what are nicotinic ACh Receptors
these are in subneural clefts that when activated lead to muscle contraction
ACh synthesis key players
choline transporter
choline acetyltransferase
what does choline transporter do?
transports choline into the cell
what does choline acetyltransferase do?
ChAT
enzyme that combines acetyle coA (AcCoA) and choline to form ACh
what do patients with Alzheimer’s disease have?
reduced cerebral production of ChAT
the enzyme that makes ACh
therapeutic is to increase levels of ACh to make up for decrease
what is ACh vesicular transporter ?
ATP dependent transporter that immediately shuttles ACh into storage vesicles after ACh synthesis
responsible for ACh storage
how many vesicles may a motor nerve terminal contain
over 300 K
ACH release happens when?
AP reaches the end of the neuron
voltage gated Ca channels open up Ca enters cell
Ca promotes vesicle membrane fusion
VAMP and SNAPs: vesicular and plasma membrane proteins that initiate vesicle-plasma membrane fusion and release of ACh
forms snare complex
Botulin/Botox does what?
can’t have fusion of vesicle and don’t have subsequent release of ACh
don’t have muscle contraction, basically having paralysis
Acetylcholinesterase
AChE
enzyme that cleaves ACh into choline and acetate
choline is recycled back into the motor neuron via the choline receptor
muscarinic Ach receptors
found on cardiac cells and smooth muscle
nicotinic ACh receptors
most important with the skeletal muscle contraction process
nicotinic ACh receptors
Activated by ACh and nicotine
Ligand-gated ion channel (Na+)
(sodium flows in upon activation–> leading to muscle AP) so very FAST
Pre- and postjunctional
NMJ: Na+ increase causes muscle action potential
mAChRs
ated by ACh and muscarine
G-protein coupled receptor
Pre- and postjunctional
NOT located at skeletal NMJ
tissue location of nA ChR and mAChR
N–> skeletal muscle
- when activated cause contraction
M—> smooth muscle , cardiac muscle (SA node, AV node, Atrium, Ventricle)
-when activated cause contraction
agonists of nAChR (cause receptor to be activated)
acetylcholine
Nicotine
agonists of mAChR
acetylcholine
muscarine
what are the functions of mAChR
Contraction of smooth muscle
cardiac--> ↓ HR ↓ conduction velocity ↓ contraction Slight ↓ contraction
parasympathetic
aceytlcholine activating muscarnic receptors
sympathetic
fight or flight, nicotinic???
what type of channels are nAChR’s and what do they allow?
ligand gated ion channels
have two binding sites for ACh
Ligand-gated ion channels allow ions to pass through the channel pore when activated
IONOTROPIC
why are the nAChR’s receptors made up of 4-5 subunits
b/c when you have a drug you only want the drug that will affect a certain receptor on a specific type of cell . allows for selectivity of drugs !!
so skeletal muscle nAChR’s are different in skeletal muscle than they are in neuronal receptors
Nm (skeletal muscle) receptor subtype of nAChR’s
activated causes excitation of skeletal muscle
main location is skeletal neuromuscular junction (postjunctional)
allows sodium ions to come in (increased cation permeability)
agonists ACh, nicotine, Succinyl-choline
nAChR postjunctional activation involves what?
Two ACh molecules bind to both binding sites
Positively charged ions (Na+, K+, Ca2+) pass through the channel
The muscle cell is depolarized and an action potential is initiated
nAChR ‘s prejunctional activation involves what?
when these are activated it allows for more vesicles to move toward the synaptic membrane
mobilization of additional ACh for subsequent release
tetrodotoxin
puffer fish): inhibition of voltage-gated Na+ channels prevents axonal conduction
if you inhibit these you can’t get action potential going down the neuron and you become paralyzed
can cause diaphragm paralysis and cannot breath
expensive in sushi b/c the chef has to prepare it correctly
local anesthetics
inhibition of voltage-gated Na channels prevents axonal conduction
blocks skeletal muscle from being activated
blocks pain going back up to brain
Batrachotoxin
(poison dart frog): causes an increase in permeability of Na+ channels and induces a persistent depolarization
One of the most potent toxins
botulinum toxin
cleaves components of the SNARE complex (VAMP/SNAP proteins)
agent that affects vesicular ACh release
agents that affect depolarization
Curare alkaloids
Succinylcholine
Snake alpha toxins
Neuromuscular blocking agents
Used for causing muscle paralysis during anesthesia induction (surgery)
Curare alkaloids
nondepolarizing competitive nAChR antagonists
succinylcholine
depolarizing nAChR agonist
snake alpha toxins
competitive irreversible inhibitor of nAChR’s
agents that inhibit AChE
Cholinesterase inhibitors
Bind to AChE and block its enzymatic activity
Increase the concentration of ACh at the NMJ
Clinical uses include dementia associated with Alzheimer or Parkinson disease, myasthenia gravis, nerve gas and organophosphate pesticide exposure, reversal of neuromuscular blockade during anesthesia
these people who have been exposed to this will have urinated themselves, tearing/watery eyes
can lead to paralysis because of the sustained activation
myasthenia gravis treatment?
give patient something that will give them more acetylcholine
give them cholinesterase inhibitor
Tetrodotoxin
blocks the outer mouth of Na+ channels and inhibits action potentials
Dantrolene
Inhibits ryanodine receptors in the sarcoplamic reticulum and blocks release of Ca2+
Clinical uses include malignant hyperthermia, spasticity associated with upper motor neuron disorders
agent that affects muscle contraction
extreme and profound activation of skeletal muscle
malignant hypothermia
how to treat? dantrolene
