L9 Neuromuscular Junction Flashcards
Neuromuscular junction
Motor neuron innervating skeletal muscle cells
Synaptic vesicles
Contain acetylcholine
Active zone
Storage and release sites for vesicles
Motor endplate
Sarcolemma opposite to synaptic terminals
Has receptors for ACh
ACh receptors
Mixed-cation channel (simultaneous Na into cell and K out of cell)
Highest concentration in junctions (synaptic) folds
End plate potential (EPP)
Depolarizing graded potential that results from the opening of ACh receptors
EPP reaches threshold and initiates action potentials
It’s nickname for graded potential
NMJ : chemical synapse
Action potential from motor neuron results in release of ACh
Opening of ACh receptors results in an EPP
The EPP depolarizes the motor endplate and initiates actions potential in muscle sarcolemma
Na and K moving though membrane but net effect is always depolarization (graded potential, varies with size of stimulus, decremental propagation, bidirectional)
Motor end plate
Region of sarcolemma of skeletal muscle with folds that are enriched with ACh receptors
Outside of motor end plate there is
Voltage gated Na and k channels that can make action potentials that travel throughout sarcolemma
Motor end plate v sarcolemma
Motor end plate: directly across from synaptic terminal, ion channels chemically gated (bind ACh), capable of EPP not action potentials
Sarcolemma: plasma membrane of muscle fiber, electrically similar to axons plasma membranes (neurons), ion channels voltage gated, propagate action potentials
Release, removal, and recycling ACh
ACh binding to receptor very brief
Acetylcholinesterase rapidly degrades ACh into choline and acetate (present in post synaptic folds of synaptic cleft)
Choline returned to presynaptic knob (recycled) reformed with acetyl-coA and in ACh
Factors affecting magnitude of EPP
Voltage gated calcium channel function
Amount ACh release
Rate of ACh breakdown
ACh receptors agonists and antagonists
Possible actions of pathophysiological conditions or pharmacological agents
Altering synthesis, axonal transport, storage, or release of neurotransmitter
Influencing neurotransmitter reuptake or destruction
Modifying or blocking neurotransmitter interaction with postsynaptic receptor (antagonist)
Replacing a deficient neurotransmitter or amplifying it’s effect with a substitute (agonist)
Non polarizing blockers
Competitively bind ACh receptor
Ion channels do not open (blockade)
Insufficient or no EPP
flaccid paralysis
Ex: curare
Blocks muscle but doesn’t depolarize
Depolarizing blockers
Prolonged activation of ACh receptor
Continuous depolarization of end plate for 2-3min
Voltage gated Na channels In sarcolemma become inactivated
Contraction follow by flaccid paralysis
Ex: succinylcholine
Permits depolarizing but consequence of prolonged depolarizing still end up blocking muscle function
Curare
Poisonous plant extract
Competitively and reversibly inhibit the nicotinic ACh receptor found at NMJ
causes weakness of skeletal muscle
Sufficient does can cause death by asphyxiation due to paralysis of diaphragm
Non depolarizing muscle blocker
Anticholinesterases
Acetylcholinesterase inhibitors
Anticholinesterase inhibits acetylcholinesterase allowing ACh to accumulate in synaptic cleft
Low doses - lacrimation, salvation, bradycardia, sweating, vomiting, diarrhea
High doses- fibrillations, muscle twitch, and depolarizing muscular paralysis
Depolarizing blocker (excessive depolarization / paralysis due to inactive Na channels)
Examples of anticholinesterases
Organophosphate pesticides and nerve gases
Neostigmine and pyridostigmine - therapeutic drugs
Anectine (succinylcholine) commonly used as a short acting depolarizing muscle relaxant to facilitate tracheal intonations
Black widow spider toxin
Contain neurotoxin: latrotoxin which form pores in the lipid membranes and induce Ca flow
Enhances neurotransmitter release (prolonged depolarization)
Symptoms: muscle spasms, intense cramping pain and generalized nervous system excitation
Very high dose - May lead to depolarizing paralysis and death
Depolarizing blocker
Lambert-Eaton syndrome
Most often seen in cancer patients
Patients exhibit proximal muscle weakness and autonomic dysfunction
Caused by autoimmune attack on voltage gated Ca channels
Fewer vesicles released in response to
presynaptic action potential and EPP is reduced
Lambert Eaton syndrome treatment
3,4-diaminopyridine blocks efflux of K ions prolonging the duration of depolarization
Keeps pathologically affect Ca channels open longer, increasing Ca influx
Change in extracellular magnesium
Mg is an essential mineral that regulates neurotransmitter release by blocking some Ca channels
Hypomagnesemia
Not enough Mg competing at Ca channels , increasing neurotransmitter exocytosis
Enhanced NMJ transmission (muscle spasms)
Causes: insufficient Mg in diet or impaired uptake
Hypermagnesemia
Too much Mg blocks Ca influx , decreasing NT exocytosis
Impaired NMJ transmission
Causes: excessive ingestion of Mg containing drugs (antacids, laxatives)
Clostridium botulinum - botulism
Anaerobic organism from soil
Sometimes found in improperly canned food
Blocks fusion of synaptic vesicles with presynaptic membrane by degradation of SNARES proteins
Targets NMJ and cholinergic nerve endings in ANS
Causes flaccid paralysis and death via respiratory paralysis
Used clinically to treat many conditions
Myasthenia gravis
Caused by autoimmune antibodies against ACh receptors = diminishes func and numbers
EPP decrease despite normal release of ACh
Symptoms : muscular weakness, blurred vision
Motor improvement with anticholinesterases (pyridostigmine)
Why does pyridostigmine provide improvement in myasthenia gravis?
It’s an anticholinesterase/ acetylcholinesterase inhibitor so it enhances ACh level at NMJ
Enhances ACh receptor interaction this improving EPP
