Neuromuscular Transmission Can Be Altered by Toxins Drugs and Trauma

The complex series of events making up neuromuscular transmission is subject to interference at several steps. Presynaptic blockade of the neuromuscular junction can occur if calcium does not enter the presynaptic terminal to participate in migration and emptying of the synaptic vesicles. The drug hemicholinium interferes with choline uptake by the presynaptic terminal and, thus, results in the depletion of ACh. Botulinum toxin interferes with ACh release. This bacterial toxin is used to treat focal dystonias (see Clinical Focus Box 9.1).

Postsynaptic blockade can result from a variety of circumstances. Drugs that partially mimic the action of ACh can be effective blockers. Derivatives of curare, originally used as arrow poison in South America, bind tightly to ACh receptors. This binding does not result in opening of the ion channels, however, and the endplate potential is reduced in proportion to the number of receptors occupied by curare. Muscle paralysis results. Although the muscle can be directly stimulated electrically, nerve stimulation is ineffective. The drug succinylcholine blocks the neuro-muscular junction in a slightly different way,- this molecule binds to the receptors and causes the channels to open. Because it is hydrolyzed very slowly by AChE, its action is long lasting and the channels remain open. This prevents resetting of the inactivation gates of muscle membrane sodium channels near the endplate region and blocks subsequent action potentials. Drugs that produce extremely long-lasting endplate potentials are referred to as depolarizing blockers.

Compounds such as physostigmine (eserine) are potent inhibitors of AChE and produce a depolarizing blockade. In carefully controlled doses, they can temporarily alleviate symptoms of myasthenia gravis, an autoimmune condition that results in a loss of postsynaptic ACh receptors. The principal symptom is muscular weakness caused by endplate potentials of insufficient amplitude. Partial inhibition of the enzymatic degradation of ACh allows ACh to remain effective longer and, thus, to compensate for the loss of receptor molecules.

Under normal conditions, ACh receptors are confined to the endplate region of a muscle. If accidental denervation occurs (e.g., by the severing of a motor nerve), the entire muscle becomes sensitive to direct application of ACh within several weeks. This extrasynaptic sensitivity is due to the synthesis of new ACh receptors, a process normally inhibited by the electrical activity of the motor axon. Artificial electrical stimulation has been shown experimentally to prevent the synthesis of new receptors, by regulating transcription of the genes involved. If reinnervation occurs, the extrasynaptic receptors gradually disappear. Muscle atrophy also occurs in the absence of functional innervation, which also can be at least partially reversed with artificial stimulation.

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