Term
| The synapses between the axons of motoneurons and skeletal muscle fibers are called ??? |
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Definition
| Neuromuscular junctions or motor end-plates. |
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Term
Overview of Neuromuscular Transmission
1) APs are propagated down the motorneuron
o Local currents depolarize each adjacent region to threshold
o Presynaptic terminal is depolarized, & this depolarization causes voltage-gated Ca++ channels in the presynaptic membrane to open
2) Ca++ permeability increases & flows into the terminal down its electrochemical gradient
3) Calcium uptake causes the release of ACh
4) ACh diffuses across the synaptic cleft to the postsynaptic membrane
o This specialized region of the muscle fiber is called the motor end plate, which contains nicotinic receptors for ACh
o ACh binds to the receptor & causes a conformational change
o This receptor is a ligand-gated channel; it is also an Na+ and K+ channel
5) When the channels open, both Na+ and K+ flow down their respective electrochemical gradients, each attempting to drive the motor end plate to its equilibrium potential. The depolarization that occurs is the EPP (see below)
6) The EPP then spreads by local currents to adjacent muscle fibers, which are depolarized to threshold & fire APs
7) The EPP at the motor end plate is terminated when ACh is degraded to choline by AchE. |
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Definition
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Term
Miniature End-Plate Potential (MEPP)
Even if a motoneuron is not stimulated, small depolarizations of the postsynaptic muscle cell occur spontaneously. These are known as miniature end-plate potentials (MEPPs). Each MEPP depolarizes the postsynaptic membrane by about 0.4 mV. A MEPP is caused by the spontaneous release of a single vesicle
of transmitter into the synaptic cleft. When MEPPs are released in a synchronous fashion, an EPP is produced. |
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Definition
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Term
o Each MEPP depolarizes the postsynaptic membrane by about 0.4 mV. An EPP is a multiple of these .4 mV units of depolarization.
How many such quanta are required to depolarize the motor end plate to the EPP???
• Because the motor end plate must be depolarized from its resting potential of -90 mV to the threshold potential of -50 mV, it must, therefore, depolarize by 40 mV
• Depolarization by 40 mV requires 100 quanta (since each quantum or vesicle depolarizes the motor end plate by .4 mV)
o A MEPP is caused by the spontaneous release of a single vesicle of transmitter into the synaptic cleft. When MEPPs are released in a synchronous fashion, an EPP is produced. |
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Definition
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Term
o End-Plate Potential (EPP)
The EPP is always large enough to initiate an action potential on the muscle membrane. It can be observed apart from the action potentials it usually triggers if its magnitude is reduced with an agent that blocks the ligand-gated channels. This reduces the magnitude of the EPP until it is less than that required to reach the muscle membrane threshold.
The EPP is NOT an AP, but simply a depolarization of the specialized motor end plate
EPPs do not regenerate like AP, it will DECAY if it does not trigger an AP |
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Definition
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Ionic Mechanism of the EPP
ACh Receptor Structure
o Consists of five subunits
These five subunits form a funnel around the mouth of a central core
When no ACh is bound, the mouth of the channel is closed
When ACh is bound to each of the 2 α subunits, a conformational change occurs in all of the subnunits, resulting in opening of the channel
Na+ flows into the cell, K+ flows out of the cell
The resulting membrane potential is midway between the Na+ and K+ equilibrium potentials, approximately 0 mVs, which is a depolarized state |
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Definition
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Term
Modification of Events in Neuromuscular Transmission
1. Procaine – local anesthetic, blocks voltage-gated Na+
2. Low ECF [Ca++] – less Ca++ to enter so NT release is effected
o High [Mg++] – can substitute for Ca++ and thus will compete as it goes through the channel
3. Botulinium toxin – blocks the release of ACh from presynaptic terminals, causing total blockade of neuromuscular transmission, paralysis of skeletal muscle, and, eventually, death from respiratory failure
4. α-bungarotoxin – binds irreversibly to ACh receptors. Used experimentally for measuring the density of Ach receptors on the motor end plate (antogonist, blocks)
o Metacholine, nicotine – bind to nicotinic receptors (they are agonists, stimulates)
6. TTX – voltage sensitive Na+ channels in muscle
• 7. Physostigmine and other anticholinergics – prevents degradation of ACh in the synaptic cleft, & they prolong & enhance the action of ACh at the motor end plate.
o Used in the treatment of myasthenia gravis |
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Definition
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Term
| True or False: Succinylcholine and curare blocks Ach from binding to its receptor. |
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Definition
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Term
Myasthenia Gravis - an autoimmune disease in which antibodies are made against the ACh receptors which decreases density of functional ACh receptors on the
postjunctional membrane. The neuromuscular junctions are incapable of transmitting signals from the nerve fibers to the muscle fibers. In some people treatment can be pharmacologic anticholinesterases), but it usually requires direct treatment of the immune problem (immunosuppressive drugs).
o Goal is to keep ACh longer in the cleft. Here are a few approaches to treatment:
- Physostigmine (AChE Inhibitor)
- Can perform a thyrectomy (because the thymus is making antibodies against the receptor)
- Can give immunosuppressive drugs |
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Definition
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Term
Denervation
o When a muscle nerve is severed, there is an immediate paralysis of that muscle.
o The muscle membrane potential then decreases, TTX-insensitive channels appear on the muscle membrane, and ACh receptors appear outside the neuromuscular junction.
o At this point, the muscle is hypersensitive to ACh and there may be spontaneous fibrillation and twitching.
o Eventually the muscle atrophies due to the loss of the trophic action of its nerve supply. The muscle is eventually replaced with fat and connective tissue
o Direct muscle stimulation with artificial electrical stimulation may slow or stop this sequence of events.
o These changes can be reversed if reinnervation occurs. |
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Definition
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