Musculoskeletal

Question 1

Explain the physiology of neuromuscular transmission

Answer 1

Skeletal muscle fibres are long, cylindrical and multinucleated 
	- Innervated by motor neuron at 'motor end plate' (specialised muscle membrane forms a series of folds). Unmyelinated terminals of the motor nerve lie in gutters on the muscle end plate
	- Motor nerve depolarisation --> ACh release into synapse --> ACh binds to NicR on muscle --> depolarisation of end plate --> action potential propagation in surrounding muscle --> muscle shortening by excitation-contraction coupling. ACh  soon metabolised by synaptic acetylcholinesterase & end plate returns to resting state

Presynaptic events:
	- Acetylcholine
		○ Synthesis- in nerve axoplasm from choline (diet + liver synthesis) + acetate 
			§ catalysed by choline-O-acetyltransferase --> this is produced in the nerve cell body and transported to the axon. Its activity is increased by steroid administration
		○ Storage - in vesicles in nerve terminal. Active transport of ACh into vesicles is by ATPases. 
			§ ~80% of neurons' ACh exists in vesicle, and this can all be released by an action potential
			§ ~20% cannot be release - forms a stationary store
	- Voltage- gated Ca channels & exocytosis
		○ Depolarisation of the presynaptic membrane results in Ca+ channel opening. Delayed opening of potassium channels results in restoration of membrane potential
			§ Release of ACh involves calcium-dependent fusion of the vesicle with the prejunctional membrane, permitting exocytosis of the contents
			§ Botulinum toxin inhibits ACh release & aminopyradines can be used to reverse this
Synaptic
	- Acetylcholine
		○ Degradation - ACh opens the NicR ion channel for only 1ms before being hydrolysed by acetylcholinesterase to choline + acetate

Postsynaptic 
	- Acetylcholine
		○ Receptors - at the NMJ, nicotinic receptors. ACh binds to α subunits on the crests of the folded motor end plate. 
		○ End plate potentials - On binding, the NicR becomes permeable to Na+, K+, Ca2+, Mg2+ & ammonium. Cation flow depolarises the membrane, resulting in an EPP rather than a popagated action potential . The localised EPP generates muscle action potentials which propagate over surrounding membrane and lead to excitation-contraction coupling
	- Excitation-contraction coupling
		○ Propagated muscle action potential produces a slower mechanical response from the muscle. Note: in cardiac muscle, contraction lasts hardly longer that the action potential