Download 19 Transmission at the Synapse and the Neuromuscular Junction

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Transmission at the Synapse and the Neuromuscular Junction
First, an orgy of nomenclature
- Inhibition can be POST-SYNAPTIC or PRE-SYNAPTIC
- DIRECT inhibition: inhibition after an inhibitory postsynaptic potential- “direct” because it is inhibition by virtue of being
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hyperpolarized by an arriving inhibitory stimulus, not because of any previous discharges of the post—synaptic cell
INDIRECT inhibition is the result of previous postsynaptic neuron discharges, eg. when the postsynaptic cell is
refractory to excitation because it just fired
PRESYNAPTIC INHIBITION AND FACILITATION happens when an inhibitory neuron sends a nerve ending to an
excitatory synapse on another neuron, and the two nerve endings form an axoaxonal synapse.
o There are 3 mechanisms of presynaptic inhibition:
 Activation of chloride channels in the PRE-synaptic neuron – that hyperpolarizes the
excitatory nerve ending and thus reduced the magnitude of excitatory action potential; and that in
turn reduces the amount of calcium that enters the excitatory nerve ending, reducing the amount of
excitatory neurotransmitter released
 Voltage-gated potassium channels can open, thus hyperpolarizing the membrane by allowing
a stream of potassium to exit, and thusa decreasing the inward calcium stream upon the arrival of
the action potential
 Direct inhibition of neurotransmitter release independent of calcium influx
GABA is a model presynaptic inhibitory neurotransmitter
o GABAA receptors are Chloride channels
o GABAB receptors are Potassium channels
Pre-synaptic facilitation also occurs andusually features a prolongation of the action potential, and
INCREASED calcium release into the cell (thus increased release of neurotransmitter)
o for example: SEROTONIN acts a presynaptic facilitator; it increases cAMP activity, which results in
phosphorylation of potassium channels (which become closed in the phosphorylated state). The result is
delayed repolarization, and thus a prolonged action potential.
ORGANISATION OF INHIBITORY CIRCUITS
A typical RENSHAW CELL: inhibitory interneuron of the spinal cord
The Renshaw cell receives input from a collateral axon of a spinal
motor neuron; it then sends a post-synaptic inhibitory signal to both
the same neuron that stimulated it ( thus exerting a negative
feedback) as well as a neighboring neuron
SUMMATION AND OCCLUSION
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SUBLIMINAL FRINGE: if neurons A and B both receive an excitatory input from the same network of endings, and A
reaches firing threshold by spatial summation (it has more excitatory endings contacfting it) then B, which is excited
but not yet at threshold, is said to be in the SUBLIMINAL FRINGE of neuron A
Neurons are said to be in the subliminal fringe if they are affected by excitatory input, but not brought to
firing thereshold ( the “discharge zone”)
OCCLUSION is the result of presynaptic endings sharing postsynaptic neurons. There is a decrease in expected
response from any given single stimulation
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THE NEUROMUSSCULAR JUNCTION
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Action
Potential
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Voltagegated Ca++
channel
Nicotinic Acetylcholine receptor
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An axon of a motor neuron loses its myelin
as it approaches a muscle fiber
It divides into several terminal boutons, or
“endfeet”, which contain acetylcholine
The endfeet fit into folds of the thickened
MOTOR END PLATE which is the part of the
muscle fiber
Only one fiber ends at one end plate; there
is no convergence of input
When an action potential arrives, ity
triggers voltage gated calcium channels
These channels activate the protein
machinery (SNAPs , synaptosomal nerve
associated proteins, and VAMPs, vesicleassociated membrane proteins) which
drags the vesicles to the surface of the
synapse
The vesicles release acetylcholine
The acetylcholine binds to the postsynaptic
acetylcholine receptor
The receptor becomes conductive to Na+
and K+
The current sink created by this brings the
adjacent membrane to firing level
The acetylcholine is rapidly degraded by
acetylcholinestrase
Acetylcholinesterase
END PLATE POTENTIAL
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The end plate contains about 15-40 million Ach receptors
Each nerve impulse releases about 60 vesicles
Each vesicle contains about 10,000 molecules of Ach
This amount is about 10 times what you actually need to reach a full end plate potential
QUANTAL RELEASE OF NEUROTRANSMITTER
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The synapse RANDOMLY releases Ach at rest.
This produces minute depolarizing spikes, each about 0.5 mV
The size of the quanta varies DIRECTLY with the Ca++ concentration and INVERSELY with Mg++ concentration
Something very similar seems to happen at all synaptic junctions
MYASTHENIA GRAVIS: antibodies to the acetylcholine receptor
LAMBERT-EATON SYNDROME: antibodies to the voltage-gated calcium channel
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NERVE ENDINGS AT SMOOTH MUSCLE
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Postganglionic neurons branch extensively over the surface of smooth muscle fibres
There are NO END PLATES
Some of the endings contain acetylcholine vesicles, other endings contain noradrenaline
There are vesicle-containing VARICOSITIES along the axons of these nerves; the neurotransmitter seems to be
released from these along the whole axon
Thus, one neuron innervates many effector cells
This is called synapse en passant- “synapse in passing”
NERVE ENDINGS AT CARDIAC MUSCLE
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Cholinergic and adrenergic fibres innervate the sinoatrial node, atrioventricular node and the bundle of His.
Noradrenergic fibers also pass into the ventricular muscle
In the ventricle, the contacts between the noradrenergic fibers and the muscle are synapses en passant
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The smooth muscles receive noradrenergic and cholinergic nerve endings; in some muscle the cholinergic is
excitatory and the noardrenegic are inhibitory; in other tissues its vice versa.
The excitatory neurotransmitter, when released, produces a small discrete partial depolarization- looks like a small
end plate potential. These are called excitatory junction potentials.
Similarly, the inhibitory neurotransmitter produces inhibitory junction potentials
These potentials are summative and can bring the cell to threshold
The potentials spread electrotonically.
JUNCTIONAL POTENTIALS
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DENERVATION HYPERSENSITIVITY
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IT IS WELL KNOWN: If you severe a nerve supply to a muscle, it becomes abnormally sensitive to acetylcholine.
The denervated skeletal muscle will also atrophy.
Smooth muscle does NOT atrophy, but does become abnormally sensitive
This is due to increased synthesis of neurotransmitter receptors.
The upregulation of receptor synthesis is due to the decreased neurotransmitter release
Hypersensitivity is limited to the structures immediately innervated by the severed neuron
References: Ganong Review of Medical physiology, 23rd ed, chapter 6