A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to function—and even just to maintain muscle tone, avoiding atrophy. In the neuromuscular system, nerves from the central nervous system and the peripheral nervous system are linked and work together with muscles. Synaptic transmission at the neuromuscular junction begins when an action potential reaches the presynaptic terminal of a motor neuron, which activates voltage-gated calcium channels to allow calcium ions to enter the neuron. Calcium ions bind to sensor proteins (synaptotagmins) on synaptic vesicles, triggering vesicle fusion with the cell membrane and subsequent neurotransmitter release from the motor neuron into the synaptic cleft. In vertebrates, motor neurons release acetylcholine (ACh), a small molecule neurotransmitter, which diffuses across the synaptic cleft and binds to nicotinic acetylcholine receptors (nAChRs) on the cell membrane of the muscle fiber, also known as the sarcolemma. nAChRs are ionotropic receptors, meaning they serve as ligand-gated ion channels. The binding of ACh to the receptor can depolarize the muscle fiber, causing a cascade that eventually results in muscle contraction. Neuromuscular junction diseases can be of genetic and autoimmune origin. Genetic disorders, such as Congenital myasthenic syndrome, can arise from mutated structural proteins that comprise the neuromuscular junction, whereas autoimmune diseases, such as myasthenia gravis, occur when antibodies are produced against nicotinic acetylcholine receptors on the sarcolemma.
Structure and function
Quantal transmission At the neuromuscular junction, presynaptic motor axons terminate 30 nanometers from the cell membrane or sarcolemma of a muscle fiber. The sarcolemma at the junction has invaginations called postjunctional folds, which increase its surface area facing the synaptic cleft. These postjunctional folds form the motor endplate, which is studded with nicotinic acetylcholine receptors (nAChRs) at a density of 10,000 receptors/μm2. The presynaptic axons terminate in bulges called terminal boutons (or presynaptic terminals) that project toward the postjunctional folds of the sarcolemma. In the frog each motor nerve terminal contains about 500,000 vesicles, with an average diameter of 0.05 micrometers. The vesicles contain acetylcholine. Some of these vesicles are gathered into groups of fifty, positioned at active zones close to the nerve membrane. Active zones are about 1 micrometer apart. The 30 nanometer cleft between nerve ending and endplate contains a meshwork of acetylcholinesterase (AChE) at a density of 2,600 enzyme molecules/μm2, held in place by the structural proteins dystrophin and rapsyn. Also present is the receptor tyrosine kinase protein MuSK, a signaling protein involved in the development of the neuromuscular junction, which is also held in place by rapsyn. About once every second in a resting junction randomly one of the synaptic vesicles fuses with the presynaptic neuron's cell membrane in a process mediated by SNARE proteins. Fusion results in the emptying of the vesicle's contents of 7000–10,000 acetylcholine molecules into the synaptic cleft, a process known as exocytosis. Consequently, exocytosis releases acetylcholine in packets that are called quanta. The acetylcholine quantum diffuses through the acetylcholinesterase meshwork, where the high local transmitter concentration occupies all of the binding sites on the enzyme in its path. The acetylcholine that reaches the endplate activates ~2,000 acetylcholine receptors, opening their ion channels which permits sodium ions to move into the endplate producing a depolarization of ~0.5 mV known as a miniature endplate potential (MEPP). By the time the acetylcholine is released from the receptors the acetylcholinesterase has destroyed its bound ACh, which takes about ~0.16 ms, and hence is available to destroy the ACh released from the receptors. When the motor nerve is stimulated there is a delay of only 0.5 to 0.8 msec between the arrival of the nerve impulse in the motor nerve terminals and the first response of the endplate The arrival of the motor nerve action potential at the presynaptic neuron terminal opens voltage-dependent calcium channels, and Ca2+ ions flow from the extracellular fluid into the presynaptic neuron's cytosol. This influx of Ca2+ causes several hundred neurotransmitter-containing vesicles to fuse with the presynaptic neuron's cell membrane through SNARE proteins to release their acetylcholine quanta by exocytosis. The endplate depolarization by the released acetylcholine is called an endplate potential (EPP). The EPP is accomplished when ACh binds the nicotinic acetylcholine receptors (nAChR) at the motor end plate, and causes an influx of sodium ions. This influx of sodium ions generates the EPP (depolarization), and triggers an action potential that travels along the sarcolemma and into the muscle fiber via the T-tubules (transverse tubules) by means of voltage-gated sodium channels. The conduction of action potentials along the T-tubules stimulates the opening of voltage-gated Ca2+ channels which are mechanically coupled to Ca2+ release channels in the sarcoplasmic reticulum. The Ca2+ then diffuses out of the sarcoplasmic reticulum to the myofibrils so it can stimulate contraction. The endplate potential is thus responsible for setting up an action potential in the muscle fiber which triggers muscle contraction. The transmission from nerve to muscle is so rapid because each quantum of acetylcholine reaches the endplate in millimolar concentrations, high enough to combine with a receptor with a low affinity, which then swiftly releases the bound transmitter.
Acetylcholine receptors
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