Physiology and Pharmocology of Skeletal Neuromuscular Junction Flashcards
describe the cells which innervate skeletal muscle
myelinated axons of motor neurones divide into unmyelinated branches near the muscle
these branches then further divide into fine branches which end in a terminal bouton which form a chemical synapse at NMJ of a single muscle cell
each unmyelinated branch supplies one muscle cell
how is an action potential transferred to a muscle cell?
AP arises in cell body and conducted along axon to the boutons which causes the release of ACh
where are the cell bodies of motor neurones found?
ventral horn of spinal cord or brain stem
where do presynaptic terminals(boutons) synapse with the muscle cells?
endplate region
name 4 key features of the NMJ
- terminal bouton and surrounding schwann cells
- synaptic vesicles
- synaptic cleft
- end plate region of muscle cell membrane (sarcolemma) thrown into junctional folds
what are active zones at the NMJ?
where vesicles containing ACh are released
at the surface of the axon terminal
where are nicotinic ACh receptors located?
at regions of the junctional folds of the end plate region
face the active zones
what are the 5 stages of synaptic transmission at NMJ?
1 = synthesis of ACh 2 = Storage of ACh in vesicles 3 = release of ACh at active zones 4 = nicotinic ACh receptor activation 5 = transmitter inactivation
how is ACh synthesised?
cholins transported into terminal via choline transporter (Na+ symport)
choline combines with acetyl coenzyme A (from mitochondria) in cytosol with help from choline acetyltransferase enzyme
how is ACh concentrated in vesicles?
vesicular ACh transporter
how is ACh released from vesicles?
arrival of the action potential at the terminal causes depolarization and opening of voltage gated Ca2+ channels allowing Ca2+ entry to the terminal
Ca2+ causes vesicles which are docked at active zones to fuse with presynaptic membrane (exocytosis)
ACh diffuses into the synaptic cleft to activate post synaptic nicotinic ACh receptors in endplate region
what are the pre and post synaptic terminals?
pre = bouton post = end plate
what are nicotininc ACh receptors made up of?
pentamer of glycoprotein subunits which surround a central cation selective pore
how does a nicotinic ACh receptor work?
pore contains a gate which is closed when ACh is absent and open when 2 ACh molecules bind to the outside
when gate open - Na+ enters, K+ leaves (equally permeable)
how is an end plate potential created?
although equally permeable to both Na+ and K+, the driving force for Na+ is greater than that for K+ at resting potential so Na+ influx exceeds K+ efflux causing a depolarization called the end plate potential
what is a quantum?
a specific amount of ACh which is contained and released from all vesicles
what is the electrical response to a quantum of neurotransmitter at the end plate?
miniature endplate potential (MEPP)
how do MEPPs cause an EPP?
many MEPPs due to many vesicles being released summates to an EPP
because the number of MEPPs can vary this means that EPP is a graded response
what does an EPP do?
depolarizes end plate region enough that a threshold is reached and an action potential is triggered (due to opening of voltage activated Na+ channels)
is an AP a graded response?
no
all or nothing
what causes an EPP?
activation of nicotinic ACh receptors in end plate
graded
what does a single action potential in a motor neuron cause in a muscle cell?
1 AP in motor neuron = 1 AP in muscle = single twitch
how can drugs cause muscle weakness/paralysis?
can reduce amplitude of EPP so AP is never triggered
why are voltage gated Na+ channels required along the muscle cell?
without them the electrical event at the end plate would decline as it spread along the muscle and wouldnt excite so contraction could not occur
Na+ channels allow the AP to propagate over whole muscle fibre
how does the muscle action potential cause contraction?
it spreads over the surface (sarcolemma) and enters transverse (T) tubules which are in close apposition to sarcoplasmic reticulum
AP arriving at the T tubule triggers release of Ca2+ from SR which then causes contraction by binding to troponin etc
how do muscle AP and contraction compare in terms of time?
AP is very brief, contraction is longer
what is the latent period?
time between AP and contraction where Ca2+ is being released from SR
what is the relaxation period?
decreasing strength of contraction as calcium is being reabsorbed into SR
what is the contraction period?
increasing strength of contraction
how is neuromuscular contraction terminated?
hydrolysis of ACh by acetylcholinesterase (AChE)
occurs in synaptic cleft
what does AChE do?
hydrolyses ACh to choline and acetate
choline reabsorbed
acetate diffuses out
how is AChE used in drugs?
nerve gas and some therapeutic agents block its action causing increased ACh in synaptic cleft and therefore increased contraction
what is neuromyotonia and how is it treated?
autoimmune disease where antibodies attack K+ channels in motor neurones causing hyperexcitability
treated with anti-convulsants which block Na+ channels
what is Lambert Eaton Myasthenic Syndrome and how is it treated?
autoimmune disease where antibodies attack Ca2+ channels in motor neurone which causes reduced vesicular release of ACh and hence muscle weakness
treatment includes anticholinesterases (anti AChE) and potassium channel blockers which increase concentration of ACh in synaptic cleft
what is myasthenia gravis and how is it treated?
autoimmune disease where antibodies attack nicotinic ACh receptors in the end plate causing reduction in amplitude of EPP and threshold therefore not reached
treatment includes anticholinesterases and immunosuppressants
what is botulinum toxin?
exotoxin that acts at motor neurone terminal to irreveribly inhibit ACh release
how does botulinum inhibit ACh release?
enters presynaptic terminal to enzymatically modify proteins involved in the docking of vesicles containing ACh at active zone, therefore preventing exocytosis
how is botulinum toxin treated?
no effective therapy
recovery takes weeks
how is botulinum used?
can be used in low doses to treat overactive muscles (dystonia) like squints
smoothing out wrinkles (botox)
what are crurare like compounds?
interfere with postsynaptic action of ACh by acting as competitive antagonists on ACh receptor
reduce amplitude of EPP to below threshold so no AP generated
how are crurare like compounds used?
clinically to induce reversible muscle paralysis in certain types of surgery
what mediates transmission at NMJ?
quantal release of ACh which acts on post junctional nicotinic ACh receptors to increase membrane cation conductance generating an EPP
