Membrane excitability is a trait that is shared by neurons and muscle fibres and that can produce action p otentials. But this trait is not exclusive to neurons and muscle fibres. For example, it is also found in glandular cells, fertilized ovules, and certain plant cells. Many toxins can affect neuromuscular junctions and their nicotinic receptors. Some toxins, such as the botulin toxin, act on the presynaptic side of the junction.
They prevent it from releasing acetylcholine and thus produce an effect of muscle weakness or paralysis. Other toxins, however, act directly on the nicotinic receptor. They occupy the acetylcholine-binding site but do not cause the channel to open. Hence the acetylcholine that has been released into the synaptic gap cannot bind to the receptors, so the muscle cannot contract.
This is how curare works the poison in which Amazon Indians dip their arrows : it kills by paralyzing the muscles of the diaphragm. This same mechanism is at work with bungarotoxin, a type of snake venom. Still other toxic substances lodge in the central channel of the nicotinic receptor, thus blocking the passage of ions.
This is what happens with procaine, lidocaine, and benzocaine, all of which are molecules used in local anesthesia, as well as with tetrodotoxin, a toxin that is found in the livers of certain fish and that can cause death within a few hours of ingestion. To make a muscle contract, the acetylcholine produced in the presynaptic neuron of the neuromuscular junction must bind to the nicotinic receptors on the postsynaptic side.
Each of these receptors consists of 5 subunits that form a pentagonal structure around a central channel. Ions and Ion Channels. The nicotinic receptor is a channel or ionotropic receptor: the same protein both forms the transmembrane channel and binds the acetylcholine or one of its agonists , such as nicotine.
When one of these substances binds to the receptor, the channel opens, allowing many sodium ions to enter the post-synaptic cell and a few potassium ions to leave it, thus depolarizing it. Individuals so poisoned die from seizures and muscle spasticity including respiratory muscles. Iontophoresis is an interesting technique that can be used to further test the hypothesis that ACh is the neurotransmitter substance at the neuromuscular junction.
If ACh is the transmitter that is released by this synapse, one would predict that it should be possible to substitute artificial application of the transmitter for the normal release of the transmitter.
Since ACh is a positively charged molecule, it can be forced out of a microelectrode to simulate the release of ACh from a presynaptic terminal. Indeed, minute amounts of ACh can be applied to the vicinity of the neuromuscular junction. The potential change looks nearly identical to the endplate potential produced by the normal release of ACh.
This experiment provides experimental support for the concept that ACh is the natural transmitter at this synapse. The response to the ejection of ACh has some other interesting properties that are all consistent with the cholinergic nature of the synapse at the skeletal neuromuscular junction.
Neostigmine makes the response to the iontophoresis of ACh longer and larger. Curare reduces the response because it competes with the normal binding of ACh.
If ACh is ejected into the muscle cell, nothing happens because the receptors for acetylcholine are not in the inside; they are on the outside of the muscle cell. Application of acetylcholine to regions of the muscle away from the end-plate produces no response because the receptors for the ACh are concentrated at the synaptic region.
To test your understanding so far, consider how an agent such as TTX would affect the generation of both an EPP and the response of a muscle fiber to the iontophoretic application of ACh?
The reason the response to ACh is unaffected is clear, but many expect that if there is no effect here, there should be no effect on the EPP either. Tetrodotoxin does not affect the binding of acetylcholine to the receptors and therefore will not affect the response to direct application of ACh.
However , tetrodotoxin will affect the ability of an action potential to be elicited in the motor axon. If an action potential cannot be elicited in the motor axon, it cannot cause the release of transmitter. Thus, tetrodotoxin would totally abolish the EPP. The block would not be due to a block of ACh receptors, but rather to a block of some step prior to the release of the transmitter.
Bernard Katz and his colleagues were pioneers in investigating mechanisms of synaptic transmission at the neuromuscular junction. A value of alpha in the GHK equation equal to one, which when substituted into the equation, yields a potential of about 0 mV. The experiment shown in the figure on the left tests that concept.
The muscle cell has been penetrated with a recording electrode as well as another electrode that can be connected to a suitable source of potential in order to artificially change the membrane potential. Normally, the membrane potential is about mV [Skeletal muscle cells have higher more negative resting potentials than most nerve cells. Katz noticed in these experiments that the size of the EPP changed dramatically depending upon the potential of the muscle cell.
If the membrane potential is moved to 0 mV, no potential change is recorded whatsoever. So three different stimuli produce endplate potentials that are very different from each other.
The lack of a response when the potential is at 0 mV is particularly informative. Consider why no potential change is recorded. Presumably, the transmitter is being released and binding to the receptors. The simple explanation for a lack of potential change is that the potential at which the opening of ACh channels are trying to reach has already been achieved.
If the membrane potential is made more positive than 0 mV, then the EPP is inverted. No matter what the potential, the change in permeability tends to move the membrane potential towards 0 mV!
If the resting potential is more negative than 0 mV, there is an upward deflection. If it is more positive, there is a downward deflection. If it is already at 0 mV, there is no deflection. This potential is also called the reversal potential , because it is the potential at which the sign of the synaptic potential reverses.
This permeability change tends to move the membrane potential from wherever it is initially towards a new potential of 0 mV. Why does the normal endplate potential never actually reach 0 mV? One reason is that the sequence of permeability changes that underlie the action potential "swamp out" the changes produced by the EPP. But even if an action potential was not triggered, the EPP still would not reach 0 mV. This is because the ACh channels are only a small fraction of the total number of channels in muscle fibers.
Their job is to try to maintain the cell at the resting potential. The channel opened by ACh is a member of a general class of channels called ligand-gated channels or ionotropic receptors. As illustrated in Figure 4.
As a result of transmitter binding to the receptor generally two molecules are necessary , there is a conformational change in the protein allowing a pore region to open and ions to flow down their electrochemical gradients.
Additional details of the channel are presented in Chapter An endplate potential in a skeletal muscle cell could in principle be produced by a decreased permeability to which of the following ions s? Assume that there is a finite initial permeability to each of the ions listed below and that physiological concentration gradients are present. An end-plate potential is a depolarization that is normally produced by the simultaneous increase in the permeability to sodium and potassium ions.
These results suggest that the trophic substance in Fr. E may be involved in the normal development of TTX-sensitive sodium channels and of acetylcholine receptor properties.
Abstract We examined the trophic effects of a partially purified trophic substance from mouse spinal cord extract on the tetrodotoxin TTX -sensitivity of action potentials and on acetylcholine-sensitivity of rat skeletal myotubes in 7- and 8-day-old cultures.
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