Clinical Note

Myasthenia Gravis

Myasthenia gravis is a debilitating neuromuscular disease associated with weakness and fatigability of skeletal muscle. The condition is aggravated by exercise. The muscular weakness and fatigability are in turn associated with EPPs that are smaller in amplitude than normal. Recall that there is generally a one-to-one relationship between an action potential in a motor axon and an action potential in the skeletal muscle cell. This is so because the EPP is normally quite large (50 mV in amplitude). As a result, an EPP in a muscle cell with a resting potential of approximately —80 mV is always capable of depolarizing the muscle cell past threshold (approximately —50 mV) and initiating a skeletal muscle action potential. Note that to reach threshold, an EPP need only have an amplitude of 30 mV (e.g., —80 mV + 30 mV = —50 mV). Thus, there is normally a safety factor of approximately 20 mV. In myasthenia gravis, the EPP is smaller and there is less of a safety factor. In severe cases, the EPP is so small that it fails to reach threshold, and no muscular contraction is produced.

The fatigability associated with myasthenia gravis is explained by the tendency for transmitter release to depress with repeated activation of a motor neuron. Such depression may be due to depletion of the pool of synaptic vesicles in the presynaptic terminal. In normal healthy adults, depression of transmitter release is of little consequence because the safety factor is so large. For example, the one-to-one relationship between motor neuron activation and skeletal muscle contraction can be maintained even if the EPP is reduced from an amplitude of 50 mV to an amplitude of 30 mV. In patients with myasthenia gravis, however, the EPP is already reduced. As a result, when the motor neuron is repeatedly activated and transmitter release is depressed, the EPP becomes subthreshold and fails to elicit an action potential in the muscle cell. Thus, whereas initial motor responses in myasthenic patients may be relatively normal, they fatigue rapidly as the EPP falls below threshold.

At the molecular level it is now known that the reduction of the EPP in patients with myasthenia gravis is due to reduction in the number of ACh receptors in the postjunctional membrane. Because of a reduced number of receptors, the postsynaptic permeability changes and the EPP are smaller. Current evidence indicates that the reduction of ACh receptors is due to an autoimmune response to the ACh receptor.

There is no known cure for myasthenia gravis. A common treatment, however, is the use of neostigmine. Neostigmine, by blocking the actions of AChE, makes more ACh available to bind with postjunctional ACh receptors and thus partially compensates for the reduced number of receptors in the myasthenic patient.


Tetany is a pathologic condition accompanying hypocalcemia (low extracellular Ca2+) that is associated with hyperexcitability of nerve and muscle cells. We have just learned that low Ca2+ tends to reduce chemical transmitter release, but low Ca2+ also has an effect on the postsynaptic cells as well (in this case, the muscle cell). Lowering the Ca2+ concentration tends to reduce the threshold for initiating action potentials. The combined effect of low Ca2+ is to make the membrane of the muscle cell easier to depolarize and thus better able to initiate action potentials, despite the decreased chemical transmitter release.

permeable to K+. The resultant depolarization may seem paradoxical, but recall that the membrane potential is due to a balance of the resting K+ and Na+ permeabilities. The K+ permeability tends to move the membrane potential toward the K+ equilibrium potential (—80 mV), whereas the Na+ permeability tends to move the membrane potential toward the Na+ equilibrium potential (+55 mV). Normally, the K+ permeability predominates and the resting membrane potential is close to, but not equal to, the K+ equilibrium potential. If K+ permeability is decreased because some of the channels close, the membrane potential will be biased toward the Na+ equilibrium potential and the cell will depolarize.

At least one reason for the long duration of slow PSPs is that second messenger systems are slow (second to minutes). Take the cAMP cascade as an example. Cyclic AMP takes some time to be synthesized but, more importantly, cAMP levels can remain elevated for a relatively long period of time (minutes) after synthesis. The duration of the elevation of cAMP depends on the actions of cAMP-phosphodiesterase, which breaks down cAMP. The duration of an effect could even outlast the duration of the change in the second messenger because of persistent phosphorylation of the substrate protein(s). Phosphate groups are removed from the substrate proteins by protein phosphatases. Thus, the net duration of a response initiated by a metabotropic receptor is dependent upon the actions of not only the synthetic and phosphorylation processes, but also the degradative and dephosphorylation processes.

The activation of a second messenger by a transmitter can have a localized effect on membrane potential through phosphorylation of membrane channels near the site of synthesis. The effects can be more widespread and even longer lasting than depicted in Fig. 25, however. For example, second messengers and protein kinases can diffuse and affect more distant membrane channels. Moreover, a long-term effect can be induced in the cell by altering gene expression. For example, PKA can diffuse to the nucleus, where it can activate proteins (e.g., transcription factors) that regulate gene expression.


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