Physiology of the Skeletal Muscle NMJ Flashcards
What innervates the skeletal muscle?
Fast conducting alpha neurons with myelinated axons and cell bodies in the spinal cord, or the brainstem
What does the axon divide into near the muscle?
Unmyelinated branches that innervate an individual muscle fibre
What do individual fibres divide into?
Multiple fine branches
What forms the chemical synapse with the muscle membrane of the NMJ?
Terminal boutons of multiple fine branches
Where are action potentials conducted to, and what do they cause?
Arise in cell body and are conducted via the axons to the boutons; causes release of acetylcholine (ACh)
What are the key structural features of the NMJ?
Terminal bouton (and surrounding Schwann cell), synaptic vesicles, synaptic cleft end plate region of sarcolemma, thrown into a series of junctional folds
Where are synaptic vesicles located?
Await release cluster in active zones (contain ACh)
Where are nicotinic ACh receptors (nAChRs) located?
At regions of the junctional folds that face the active zones
What are the key steps of neuromuscular transmission?
Synthesis of ACh in cytoplasm of bouton
Uptake of ACh into synaptic vesicles for concentration and storage
Ca2+ dependent release of ACh into synaptic cleft by exocytosis
Brief activation of nAChRs by reversible binding of ACh
Rapid termination of transmitter action by acetylcholinesterase within the synaptic cleft
What transports choline into the terminal?
Choline transporter (symport with Na+)
Where is ACh synthesised?
In the cytosol from choline and acetyl Co-A by acetyltransferase
What concentrates ACh in the vesicles?
Vesicular ACh transporter
What does arrival of the action potential at the terminal cause?
Depolarisation
Opening of voltage-activated Ca2+ channels
Ca2+ entry to the terminal
What does Ca2+ cause the vesicles to do?
Causes vesicles docked in active zones to undergo exocytosis
What does ACh do once it has diffuses into the synaptic cleft after being released from the vesicle?
Activates post-synaptic nAChRs in the end plate region
How many ACh molecules are needed to activate each nAChR?
Two ACh molecules
What are nAChRs?
Pentamers of glycoprotein subunits [(alpha 1)2 beta 1 delta elsilon] surrounding a central action pore (formed by M2 helices)
What does the pore present in nAChRs contain?
A gate that is closed in the absence of ACh, but opens when ACh binds to the exterior of the receptor at the subunit interface
What is a feature of the gate present in nAChRs?
Roughly equally permeable to Na+ and K+ but doesn’t conduct anions
What happens when the nAChR gate is open?
Simultaneous Na+ influx and K+ efflux
Why is Na+ influx greater than K+ efflux?
The driving force of Na+ is greater than that of K+ at resting membrane potential
What is generated by the simultaneous opening of many nAChRs?
A depolarising endplate potential (e.p.p)
What does each vesicle of ACh contain?
A quantum of neurotransmitter
What does one quantum produce in response to activation of nAChRs at the endplate?
The electrical response of one quantum of transmitter is a miniature endplate potential (m.e.p.p)
What do many m.e.p.ps produce?
Summate to produce the e.p.p, a graded electrotonic response
What does an e.p.p greater than threshold trigger?
“All or nothing” propagated action potential that initiates contraction (this always occurs normally)
What happens if an e.p.p is less than threshold?
Neither elicits action potential not contraction
What does the e.p.p. trigger in Na+ channels?
Causes opening of voltage-activated Na+ channels, generating an action potential
What is the e.p.p?
Graded response determined by the number of vesicles released
What does one action potential in the motor nerve trigger?
One action potential in the muscle (one-to-one coupling) and a subsequent contraction of the muscle fibre
What do drugs that reduce the e.p.p to beneath threshold do?
Block neuromuscular transmission because no muscle action potential is generated
What are muscle action potential needed to do?
Needed to propagate the response over the length of the fibre using voltage-activated Na+ channels
What does the muscle action potential cause?
Contraction due to the release of Ca2+ from the sarcolemma of the skeletal muscle cells
Where does the muscle action potential propagate to over the sarcolemma?
Into T-tubules
What are T-tubules?
Invaginations of sarcolemma that dip deeply into muscle cell
What are the T-tubules in close opposition with?
The sarcoplasmic reticulum
What does the action potential arriving at T-tubules trigger?
Release of Ca2+ from the sarcoplasmic reticulum, which in turn causes contraction by interacting with troponin associated with myofibrils
What is the rapid termination of neuromuscular transmission a result of?
Hydrolysis of Ach by acetylcholinesterase to choline and acetate
What is acetylcholinesterase?
An enzyme associated with the endplate membrane
What happens to choline and acetate once they have been produced by hydrolysis of ACh?
Choline taken up by choline transporter, acetate diffuses from synaptic cleft
How is acetylcholinesterase efficient?
Some Ach molecules hydrolysed even prior to transmitter binding to nAChRs, once unbinding occurs virtually all Ach molecules are hydrolysed
What is the result of acetylcholinesterase’s efficiency?
Rebinding is limited and the e.p.p I terminated within a few milliseconds
What are some substances that target acetylcholinesterase?
Anti-cholinesterases = reversibly block action of acetylcholinesterase
Insecticides
Nerve gases = act irreversibly
What are some symptoms of neuromyotonin (Isaac’s disease)?
Cramps, stiffness, slow relaxation (myotonia), muscle twitches (fasiculations)
What is the cause of the acquired form of neuromyotonin?
Antibodies attack voltage-gated K+ channels in the motor neuron, disrupting function causing hyperexcitability repetitive firing
What does the repetitive firing in neuromyotonin cause?
Prolonged e.p.p and repetitive action potential discharge in skeletal muscle fibres?
How are anticonvulsants used to treat neuromyotonin?
Block voltage-activated Na+ channels (e.g carbamazepine, phenytoin)
What characterises Lambert-Eaton myasthenic syndrome?
Muscle weakness in the limb (very rare and associated with small cell carcinoma of lung)
What causes Lambert-Eaton myasthenic syndrome?
Antibodies against voltage-activated Ca2+ channels in the motor neuron terminal results in reduces Ca2+ entry in response to depolarisation (also reduced vesicular release of ACh)
What are some drugs used to treat Lambert-Eaton myasthenic syndrome?
Anticholinesterases (e.g pyridostigmine) = increase the duration of ACh action potential in synaptic cleft
Potassium channel blockers (e.g 3,4-diaminopyridine) = increase release of ACh by prolonging action potential in motor neuron terminal
What are the characteristics of myasthenia gravis?
Increasing muscle weakness during periods of activity, often weakness of eye and eyelid muscles is a presenting feature
What causes myasthenia gravis?
Antibodies against nAChRs in the endplate results in the reduction in the number of functional channels and hence amplitude of e.p.p
What are some drugs used to treat myasthenia gravis?
Anticholinesterases (e.g edrophonium, pyridostigmine) = increase ACh concentration in synaptic cleft
Immunosuppressives (e.g azathioprine)
What is botulinum toxin?
Extremely potent exotoxin (related to tetanus and diptheria toxins) that acts at motor neuron terminals to irreversibly inhibit ACh release
How does botulinum toxin prevent exocytosis of vesicles containing ACh?
Enters presynaptic nerve terminal to enzymatically modify proteins involved in docking of vesicles containing ACh
What is the prognosis of botulism?
Death rate high, recovery takes several weeks, drugs that block acetylcholinesterase are useless as therapeutic agent
What are some clinical and cosmetic uses of botulinum toxin?
Low dose botulinum haemoglutin complex delivered by IM injection to treat overactive muscles (dystonias)
Used to smooth out age-related wrinkles by paralysing muscles
What do curare-like compounds act as?
Competitive antagonists of nAChrs = interfere with postsynaptic action of ACh (e.g vecuronium atracurium)
How do curare-like compounds affect the e.p.p?
Reduce amplitude to below threshold for muscle fibre action potential generation
How are curare-like compounds used clinically?
Induce reversible muscle paralysis in certain types of surgery
