Neuromuscular Transmission
- neuromuscular transmission: chemically-mediated process by which motor neurons communicate with muscles
- summary of neuromuscular transmission
- storage: acetylcholine concentrated in vesicles
- release: action potential signals vesicle release by exocytosis
- synapse: acetylcholine crosses junctional cleft, bunds receptors
- potentiation: bound acetylcholine alters endplate potential (EPP)
- firing: sum of EPP cause post-synaptic action potential
structure of the neuromuscular junction
- motor unit: motor neuron plus all muscle fibers it innervates (set up for synchronous muscle contraction)
- motor neuron anatomy
- axon myelination: myelinated for most of length, but unmyelinated near muscle fibers
- motor endplate: region of the fiber underlying the axon terminal
- junctional cleft: synaptic cleft 20-50 nm across (larger than a CNS synapse)
- active zones: specialized presynaptic structures where exocytosis takes place
- junctional folds: postsynaptic membrane invaginations opposite presynaptic active zones
- specializations for speed, reliability
- many vesicles per bouton
- many active zones, with high probability of release
- high density of postsynaptic nAChRs
- neuromuscular transmission
- acetylcholine: transmitter used in motor neuron synapse
- endplate potential (EPP): depolarizing postsynaptic potential created at motor endplate
- nicotinic acetylcholine receptors (nAChR): responsible for binding of acetylcholine
- density: 7,500 – 50,000 /mm2
- structure: ligand-gated ion protein complex
- lamina basilaris: extracellular matrix at motor neuron synapse, extending into the cleft, filling postsynaptic folds
- function: maintain structure of junctional folds
- acetylcholinesterase: enzyme that inactivates acetylcholine and terminates signal; located in lamina basilaris
- note: in CNS, most neurotransmitter action is terminated by diffusion, reuptake
prejunctional elements
- acetylcholine synthesis: localized in the axon terminals
- reaction: 
- choline-acetyltransferase (ChAT): enzyme responsible for acetylcholine synthesis
- ChAT synthesis: motor neuron soma
- ChAT localization: motor neuron axon terminals
- choline: synthesized in liver, concentrated in nerve terminal via ATP-dependent pumps
- acetyl-CoA: synthesized from pyruvate à acetate à acetyl-CoA
- acetylcholine release is quantal
- mechanism: Ca2+ influx via voltage-gated Ca2+ channels
- vesicle localization: concentrated in active zones of the prejunctional membrane
- each contains 6,000 – 10,000 molecules of acetylcholine
- each action potential causes release of 200-300 vesicles into the junctional clefts
- reducing acetylcholine release
- reduction in extracellular Ca2+
- increase in Mg2+
- use of local anesthetics (block AP in the motor axon)
- botulinum toxin (interferes with Ca2+-mediated exocytosis)
- spontaneous release
- mechanism: spontaneous, random vesicular fusion (does not require Ca2+)
- miniature endplate potential (mEPP): postjunctional potential caused by single quanta of acetylcholine
postjunctional elements
- binding of acetylcholine to postjunctional receptors
- postjunctional delay: 0.5 msec
0.00 to 0.30 msec: release of transmitter
0.30 to 0.35 msec: diffusion across the junctional cleft
0.35 to 0.50 msec: occupation of the receptor
channel opening and capacitive charging of the membrane
- acetylcholine concentrations
- pattern: sharp rise, rapid decline
- acetylcholine fates
- binding to receptors
- binding to acetylcholinesterase
- diffusion
- the acetylcholine receptor is a ligand-gated ion channel
- structure
- 5 subunits (α,α,β,δ,γ), 2 ACh binding sites
- mechanism: binding of ACh causes conformational change that opens the ion channel
- specificity: Na+, K+
- desensitization of a ligand-based channel
- desensitization: process by which net depolarizing current gradually declines despite continued ACh binding
- 3 conformations: resting, open, desensitized (R à O à D)
- analogous to closed, open, inactive (C à O à I) of voltage-gated channels
- under physiological conditions, ACh not maintained in the cleft
- the endplate potential
- endplate potential (EPP): postjunctional synaptic response to ACh
- always gives rise to action potential in the muscle membrane, under physiological conditions
- size: depolarization of 30-40 mV (from resting -80 mV)
- origin: temporal, spatial summation of individual mEPPs from single quanta of ACh
- mechanism: increased PNa, PK, causing a net Vm depolarization (yielding an excitatory effect)
- action potential
- process
- nAChR: acetylcholine-sensitive; generates endplate potential (EPP)
- EPP: depolarizing; generates action potential in adjacent regions of the muscle membrane
- AP threshold: -55 mV
- high safety factor: under physiological conditions, each EPP will give rise to an AP
- transmitter action is terminated by ACh hydrolysis and diffusion
- acetylcholinesterase: primary mechanism of inactivation
- some acetylcholine is hydrolyzed even before binding the postjunctional membrane
- most binds the postjunctional membrane, must dissociate before being hydrolyzed
- choline: hydrolysis byproduct that is taken up by the presynaptic axon terminal to be recycled
- diffusion: secondary mechanism of inactivation
- escaping ACh is broken down by serum cholinesterases
mechanisms of blockade of neuromuscular transmission
- competitive blocking agents: inhibition of ACh binding
- competitive antagonist: binds ACh site without opening channel
- gallamine: competitive antagonist that is useful in surgical procedures
- depolarizing blocking agents: production of a refractory state
- agonist: binds ACh and also opens channel
- dissociate more slowly, leading to sustained depolarization and inactivation of the postjunctional neuron
- also lead to desensitization of receptor
- succinylcholine: depolarizing blocker useful for induction of short-term paralysis in surgical procedures
- anticholinesterases: subclass of depolarizing blocking agents
- cause accumulation of ACh, leading to depolarization block and desensitization
- function
- clinical: facilitate termination of neuromuscular blockade by competitive blockers (e.g. gallamine)
- warfare: nerve gases; can cause paralysis of muscles that facilitate respiration
- myasthenia
- myasthenia: a collection of neuromuscular disorders characterized by degenerative muscle weakness
- autoimmune: antibodies produced against AChR, interfere with binding
- congenital: lack of acetylcholinesterase
- slow-channel congenital myasthenic syndrome (SCCMS): dominant disorder of neuromuscular junction
No comments:
Post a Comment