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INTRODUCTION

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Signals from the motor neuron cross a chemical synapse, the neuromuscular junction, to the muscle fiber to produce muscle contraction. This complex process involves action potentials, numerous ion channels, the neurotransmitter acetylcholine (ACh), and receptors. Several medications, toxins, and disease states affect the integrity of transmission.

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TRANSMISSION AT THE MOTOR NEURON

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The motor neuron’s axon receives an action potential leading to depolarization of the presynaptic terminal. “Active zones” of the presynaptic terminal contain high concentrations of voltage-dependent Ca2+ channels, mitochondria, and presynaptic vesicles containing ACh. Upon depolarization, these voltage-gated Ca2+ channels open, causing an influx of calcium into the nerve terminal. Ca2+ influx induces the cascade that begins with phosphorylation of proteins called synapsins, which keep vesicles containing ACh in a presynaptic actin network. Once this cascade starts, presynaptic vesicle release from the actin network begins, allowing presynaptic membrane fusion. Vesicle contents, which include ACh, are subsequently released into the synaptic cleft via exocytosis.

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TRANSMISSION AT THE SYNAPSE

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Acetylcholine diffuses across the 30-50 nm synaptic cleft to reach its target, nicotinic receptors, on the postjunctional muscle fiber. Some of the neurotransmitter is lost and some is inactivated before reaching the postjunctional membrane.

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TRANSMISSION AT THE MUSCLE FIBER

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Once ACh reaches the postjunctional membrane, it binds to nicotinic ACh receptors, which are permeable to Na+ and Ca2+. Binding of ACh to these receptors causes a conformational change, allowing Na+ and Ca2+ influx into the cell. These receptors are also permeable to K+ (although to a lesser extent), which flows out of the cell. Acetylcholine binding cation influx causes a miniature end-plate potential (MEPP) in which the cell starts to become depolarized. If several vesicles are released, the MEPPs summate to generate an end-plate potential of the muscle fiber that leads to an action potential if large enough. This action potential spreads among the plasma membrane and T-tubule system, causing release of Ca2+ from the sarcoplasmic reticulum and ultimately muscle contraction.

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Acetylcholine is rapidly degraded by acetylcholinesterase to prevent reexcitation of muscle. The ion channels on the postsynaptic membrane close following ACh reduction, thus repolarizing the cell and causing muscle relaxation.

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MEDICATIONS AND TOXINS

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Curare was the first muscle relaxant to be introduced. Since then, synthetic compounds derived from curare have been used for muscle relaxation in surgical settings. Curare works by binding ACh receptors and preventing ACh from acting upon them. Both nondepolarizing and depolarizing muscle relaxants work at the neuromuscular junction. Nondepolarizing agents work by competitively binding either one or both of the alpha subunits on the ACh receptor located on the postjunctional membrane. This prevents receptor opening and depolarization. Depolarizing agents, namely succinylcholine, work by binding the alpha subunits and mimicking ACh to prolong the depolarized state. This causes muscle ...

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