NMJ - synaptic transmission Flashcards
what is the NMJ?
neuromuscular junction
the contact between a motor neuron and muscle cell
converts electrical energy into mechanical force
specialised for fast and reliable control of muscle contraction
Why is the NMJ the prototypical model system for studying synaptic structure and function?
each skeletal muscle cell receives a single synaptic input from one motor axon
muscle cell is large and easy to record from
single efferent axon can be excited using simple electrical stimulation
(in CNS neurons receive many convergent synaptic inputs which are individually small and weak)
what is the synaptic cleft
the small gap between the presynaptic neuron and the postsynaptic muscle fibre
(suggestive of chemical diffusion)
what are the criteria for identifying a chemical as a neurotransmitter
must be present within the presynaptic neuron
must be released in response to presynaptic stimulation
specific receptors for the substance must be present on the postsynaptic cell
agonists of the receptors must mimic the synaptic response
antagonists must block the synpatic response
what is the neurotransmitter in the NMJ
acetylcholine (ACh)
what are the advantages of chemical synaptic transmission
can be readily modulated by other transmitters
can be excitatory or inhibitory
impedence matching (muscle cell is much larger than the motor afferent so the small current in the presynaptic terminal would not be sufficient to evoke a muscle action potential)
What is the EPP
end-plate potential
endplate: area of the muscle cell that receives synaptic input (hyperpolarised at rest)
endplate potential: stimulation of the efferent motor axon evokes a large synaptic depolarisation (the depolarisation is the EPP)
EPP decreases with distance from the endplate
indicates passive propagation so the muscle excitation initiated at the endplate of the NMJ triggers an action potential which actively propagates through the cell
What are the ACh receptors?
nicotinic acetylcholine receptors (nAChR)
ligand-gated ion channels that bind ACh
generate the EPP
composed of 5 subunits (mature nAChRs at the NMJ contain two α subunits and β, δ and ε
subunit)
permeable to cations
what is distinctive about the motor endplate
junctional folds
the nAChR are expressed at high density at the crests of the folds
voltage-gated Na+ channels are located at the base of the folds
increase SA
ensure maximal sensitivity to detect ACh release
maintain high density of Na+ channels in close proximity to the synapse
makes EPP triggering of action potential reliable
what is the significance of Ca2+
action potential in the presynaptic nerve terminal opens voltage-gated Ca2+ channels causing influx of Ca2+
increase in presynaptic [Ca2+] triggers neurotransmitter release
reducing [Ca2+] outside decreases release and the EPP amplitude
logEPPamp against log[Ca2+]out - straight line with slope of 4
release is proportional to ([Ca2+]out)^4
Ca2+ sensors may need to bind 4Ca2+ ions in order to trigger release
what are mEPPS
miniature endplate potentials
spontaneous activity in endplate in the absence of presynaptic action potentials
same shape as EPPs but are 0.5mV rather than 50mV
each have similar amplitude
blocked by nAChR antagonists (curare)
the structural correlate of mEPPs are the vesicles of neurotransmitter packed into the presynaptic terminal
what is the quantal nature of evoked synaptic transmission
ACh is spontaneously released in small packets of a fixed size - quanta follows binomial statistics p= probability of qunatal release q= amplitude n= number of release sites npq = mean response
What is the vesicle cycle
neurotransmitters are actively transported into synaptic vesicles
synaptic vesicles cluster in front of the active zone
synaptic vesicles dock at the active zone
vesicles are primed for Ca2+ triggered fusion-pore opening
following fusion-pore opening synaptic vesicles endocytose and recycle by three alternative pathways
a. kiss and stay: vesicles are reacidified and refilled with neurotransmitters without undocking (readily reusable)
b. kiss and run: vesicles undock and recycle locally to reacidify and refill with neurotransmitter
c. vesicles endocytose via clathrincoated pits
they reacidify and refill with neurotransmitter either directly or after passing through an endosomal intermediate
what is the significance of fusion pore opening?
unlikely to influence release but are important for endocytosis
fast recycling may preferntially utilise transient fusion pores
slow recycling involves a full collapse of the vesicle into the plasma membrane
synaptic vesicles are so small that even an unstable fusion pore will empty rapidly
how is neurotransmitter in the NMJ transferred to vesicles?
ACh is transferred into synaptic vesicles by the vesicular acetylcholine transporter (VAChT)
vesicles are acidified by accumulating H+
VAChT exchanged ACh for H+
