Acetylcholine muscle action potential

Takahashi, M., Kubo, T., Mizoguchi, A., Carlson, C. G., Endo, K. and Ohnishi, K. (2002) Spontaneous muscle action potentials fail to develop without fetal-type acetylcholine receptors. EMBORep 3, 674-681. 

The acetylcholine diffuses across the gap between the nerve terminal and the muscle membrane, (the neuromuscular cleft) and binds to receptors on the muscle surface. This results in the opening of Na /K channels and Na flows down its concentration gradient into the muscle. This ion flux causes a localised depolarisation, termed an "endplate potential", in the muscle. This nerve-evoked electrical disturbance can be measured using a microelectrode inserted into the muscle cell at the neuromuscular junction region and compared to a reference electrode. When the amplitude of this depolarisation reaches a threshold level a regenerative electrical depolarisation, known as an "action potential" is triggered in the muscle. This action potential is transmitted into the muscle cell where it triggers contraction of the muscle fibre. At the mammalian neuromuscular junction there is normally a 1 1 relationship between nerve action potentials and muscle action potentials. 

Voluntary muscle contraction is initiated in the brain-eliciting action potentials which are transmitted via motor nerves to the neuromuscular junction where acetylcholine is released causing a depolarization of the muscle cell membrane. An action potential is formed which is spread over the surface membrane and into the transverse (T) tubular system. The action potential in the T-tubular system triggers Ca " release from the sarcoplasmic reticulum (SR) into the myoplasm where Ca " binds to troponin C and activates actin. This results in crossbridge formation between actin and myosin and muscle contraction. 

Each muscle fiber is innervated by a branch of an alpha motor neuron. The synapse between the somatic motor neuron and the muscle fiber is referred to as the neuromuscular junction. Action potentials in the motor neuron cause release of the neurotransmitter acetylcholine. Binding of acetylcholine to its receptors on the muscle fiber causes an increase in the permeability to Na+ and K+ ions. The ensuing depolarization generates an action potential that travels along the surface of the muscle fiber in either direction that is referred to as a propagated action potential. This action potential elicits the intracellular events that lead to muscle contraction. 

At the neuromuscular junction, the terminus of the axon is separated from the sarcolemma by a cleft about 4 nm wide. When an action potential arrives at the terminus, it activates a voltage-sensitive Ca " ion channel. This results in Ca + ions diffusing into the terminus increasing the intracellular Ca + ion concentration, which stimulates exo-cytosis of acetylcholine from the terminus into the cleft. The acetylcholine diffuses across the cleft and binds to receptors on the motor end-plate (Figure 13.12) on the muscle side of the cleft. The binding of acetylcholine to... 

Figure 13.12 motor end-plate. The axon terminates very close to the muscle. They are separated by a small gap (the synaptic cleft). When the nerve is stimulated, acetylcholine is released into the cleft where it diffuses across the cleft, and then binds to receptors located on the muscle side of the cleft and initiates an action potential along the sarcolemma. 

Figure 13.16 A summary of the control of muscle contraction by the motor neurone. When an electrical impulse arrives at the junction between a nerve axon and a muscle fibre, a small amount of acetylcholine is released. This initiates an action potential which is transmitted throughout the fibre via the T-tubules. This causes the sarcoplasmic reticulum to release Ca ions which initiate contraction of the myofibrils via changes in troponin and tropomyosin. Thus sites on the actin for binding of the myosin cross-bridges are exposed.

Neuromuscular transmission (B) of motor nerve impulses to the striated muscle fiber takes place at the motor endplate. The nerve impulse liberates acetylcholine (ACh) from the axon terminal. ACh binds to nicotinic cholinocep-tors at the motor endplate. Activation of these receptors causes depolarization of the endplate, from which a propagated action potential (AP) is elicited in the surrounding sarcolemma. The AP triggers a release of Ca from its storage organelles, the sarcoplasmic reticulum (SR), within the muscle fiber the rise in Ca concentration induces a contraction of the myofilaments (electromechanical coupling). Meanwhile, ACh is hydrolyzed by acetylcholinesterase (p. 100) excitation of the endplate subsides. if no AP follows, Ca + is taken up again by the SR and the myofilaments relax. 

Muscle contraction is triggered by motor neurons that release the neurotransmitter acetylcholine (see p. 352). The transmitter diffuses through the narrow synaptic cleft and binds to nicotinic acetylcholine receptors on the plasma membrane of the muscle cell (the sarcolemma), thereby opening the ion channels integrated into the receptors (see p. 222). This leads to an inflow of Na which triggers an action potential (see p. 350) in the sarcolemma. The action potential propagates from the end plate in all directions and constantly stimulates the muscle fiber. With a delay of a few milliseconds, the contractile mechanism responds to this by contracting the muscle fiber. 

Beside this there are some major differences with the neurotransmission in the autonomous nervous system The contractile activity of the skeletal muscle is almost completely dependent on the innervation. There is no basal tone and a loss of the innervation is identical to a total loss in function of the particular skeletal muscle. In contrast to the target organs of the parasympathetic nervous system the skeletal muscle cells only have acetylcholine receptors at the site of the so-called end-plate, the connection between neuron and muscle cell with the rest of the cell surface being insensitive to the transmitter. The release of acetylcholine results in a postjunctional depolarization which is either above the threshold to induce an action potential and a contraction or below the threshold with no contractile response at all. In contrast to the graduated reactions of the parasympathetic target organs, this is an all or nothing transmission. 

Neuromuscular transmission. Transmitter release at the motor nerve terminal occurs by exocytosis of synaptic vesicles that contain acetylcholine (ACh). The process is enhanced by an action potential that depolarizes the membrane and allows Ca++ entry through channels at the active sites. ACh may be hydrolyzed by acetylcholinesterase (AChE) or bind to receptors (AChRs) located at the peaks of the subsynaptic folds. Simultaneous activation of many AChRs produces an end plate current, which generates an action potential in the adjacent muscle membrane. 

At the neuromuscular junction, the electrical changes following the action of the neurotransmitter substance acetylcholine on the muscle cell were investigated by Katz and Fatt in 1951. It was reasonable to suppose that the ionic currents passed through channels that were activated by acetylcholine. Both here and with the nerve action potential only the currents produced by flow through some hundreds or thousands of channels at once could be measured. 

Release. Certain drugs will increase synaptic activity by directly increasing the release of neurotransmitter from the presynaptic terminal. Amphetamines appear to exert their effects on the CNS primarily by increasing the presynaptic release of catecholamine neurotransmitters (e.g., norepinephrine). Conversely, other compounds may inhibit the synapse by directly decreasing the amount of transmitter released during each action potential. An example is botulinum toxin (Botox), which can be used as a skeletal muscle relaxant because of its ability to impair the release of acetylcholine from the skeletal neuromuscular junction (see Chapter 13). 

Succinylcholine, similar to acetylcholine, interacts with the cholinergic receptors at the end plate region of the muscle, resulting in depolarization of the chemically excitable membrane. This, in turn, creates local action potentials, spreading them to and depolarizing the adjacent excitable membranes, finally culminating in a muscle contraction, or fasciculation, which is an uncoordinated muscle contraction. However, unlike acetylcholine, succinylcholine is not metabolized by acetylcholinesterase, and hence causes persistent depolarization of the end plate. The continuous presence of succinylcholine leads to inexcitability of the membrane adjacent to the end plate, resulting in... 

Once the neurotransmitter is released from the presynaptic terminal it diffuses across the synaptic cleft. On the postsynaptic side it complexes with a membrane-bound macromolecule, its receptor. In synapses that have to generate action potentials within microseconds of neurotransmitter release, the receptors must be clustered in the postsynaptic membrane at high density, close to where the neurotransmitter is released. Such a synapse exists at the neuromuscular junction, where acetylcholine is the neurotransmitter. Acetylcholine is released from the presynaptic nerve terminal within 50 nm of the postsynaptic muscle membrane that contains densely arrayed acetylcholine receptors ( 10,000 acetylcholine rcccptors/pm2). There is a steady turnover of receptors, with newly synthesized receptors replacing those that are periodically degraded or not being utilized. 

The neuromuscular junction is the synapse (junction) of an axon terminal of a motorneuron, which terminates in a depression of the sarcolemma (the cell membrane of a muscle cell), the motor end plate. It is here that the initiation of action potentials across the muscle surface ultimately leads to muscle contraction. In vertebrates, the neurotransmitter is acetylcholine. 

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