THE BRAIN FROM TOP TO BOTTOM

Making a Voluntary Movement

Even at rest, most of your muscles are in a state of partial contraction called muscle tonus. This tonus is maintained by the constant activation of a small number of motor units that contract alternately.

The muscle fibres that make up a particular motor unit are not physically located right next to each other, but rather scattered at various locations in the muscle. This arrangement makes functional sense when you consider how much energy must be provided to make a muscle contract. This energy comes from the combustion of glucose, which is carried to the muscle fibres by the blood capillaries running between them. Since by definition, all the muscle fibres making up a given motor unit are innervated by the same motor neuron and contract at the same time, if they were physically adjacent, then when they contracted, their thickening would compress the capillaries supplying them with energy. This sudden reduction in their energy supply would produce rapid fatigue in the motor unit. The scattered distribution of the unit's fibres throughout the muscle avoids this problem.

THE ROLE OF THE NEUROMUSCULAR JUNCTION IN MUSCLE CONTRACTION

The contraction of a motor unit in a muscle is initiated by the release of acetylcholine into the neuromuscular junction.

The acetylcholine activates cholinergic nicotinic receptors in the motor end plate of the muscle fibre, triggering an excitatory potential in its post-synaptic membrane, the sarcolemma. If this potential reaches a certain threshold, a muscular action potential is generated by the potential-dependent sodium channels in this membrane.

This action potential travels first over the surface of the sarcolemma and then over that of the T tubules, causing calcium stored in the sarcoplasmic reticulum to be released. This calcium diffuses into the myofibrils, which are divided by Z stripes into segments called sarcomeres. In each sarcomere, thick and thin filaments then slide past each other, thus drawing the Z stripes closer together, reducing the length of the sarcomere, and causing the muscle to contract.

To understand how the calcium causes these thick and thin filaments to slide past each other, we must consider the proteins of which they are composed. The thick filaments consist mostly of myosin, while the thin filaments consist mostly of actin. Each myosin molecule has a "head" at either end, including a site that can bind with actin.

When no calcium is present, the myosin in the thick filaments cannot bind with the actin in the thin ones, because the binding sites on the actin molecules are occupied by another protein, troponin. But when calcium is released by a muscular action potential, it binds to the troponin, thereby accomplishing two things: 1) exposing the actin-binding sites on the myosin molecule heads; and 2) altering the form of another protein, tropomyosin, so that it exposes the myosin-binding sites on the actin molecules.

The myosin heads can then bind to the sites on the actin molecules. In this process, these heads undergo a change in conformation that makes them rotate. It is this rotation that pulls the thin actin filaments past the thick myosin filaments, one notch at a time, like a ratchet mechanism, causing the muscle to contract.

The contraction will continue as long as calcium and ATP are available. One of the functions of the ATP is to break the bond between the myosin and the actin. (This explains why the muscles of a dead body become rigid as the supply of ATP begins to run short.)

The amount of calcium released by the sarcoplasmic reticulum depends on the frequency of the action potentials in the muscle fibre. (If this frequency reaches or exceeds 50 stimuli per second, it is high enough to cause a sustained muscle contraction, known as a tetanus.)

The muscle contraction ends when the action potentials cease and the concentration of calcium in the myofibrils diminishes. This reduction in calcium is due to its being recaptured by the sarcoplasmic reticulum, an active process that requires ATP. When the calcium concentration returns to normal, the muscle fibre returns to its relaxed position.

Myasthenia gravis is a disease associated with a malfunction in the transmission of impulses from the nerves to the voluntary muscles. It is considered an auto-immune disease, because in patients who have it, certain white blood corpuscles manufacture antibodies against the body's own acetylcholine receptors, thus destroying them. The efficiency of the neuromuscular junctions is thereby reduced, causing muscle weakness during physical effort or, in the most serious forms of the illness, a permanent reduction in muscle strength.

Certain toxic gases such as sarin act by preventing acetylcholinesterase from hydrolyzing acetylcholine, thus causing constant stimulation of the receptors and violent muscle spasms.

Miniature electrical currents, each corresponding to the spontaneous release of one acetylcholine (ACh) vesicle, can be recorded at the postsynaptic motor end plate of the neuromuscular junction in the absence of any stimulation of the presynaptic motor axon. Each of these miniature currents corresponds to the opening of about 1 600 nicotinic receptor channels by the effect of ACh. Since it takes two ACh molecules to open one such channel, it follows that one vesicle contains 3 200 molecules of ACh. The spike in the current at the motor end plate represents about 100 miniature currents, or the release of about 320 000 molecules of ACh opening about
160 000 nicotinic receptors.

NICOTINIC ACETYLCHOLINE RECEPTORS

At the neuromuscular junction, acetylcholine is synthesized in the cytoplasm of the axon's terminal button, from acetyl coenzyme A and choline. (About half of this choline has been recaptured by the terminal button after previously produced acetylcholine was hydrolyzed by the enzyme acetylcholinesterase in the synaptic gap.) Many thousands of molecules of acetylcholine are thus stored in each synaptic vesicle (see sidebar).

As soon as the vesicles' contents are released into the synaptic gap, about half of the acetylcholine molecules are hydrolyzed by acetylcholinesterase. But soon so many acetylcholine molecules accumulate that this enzyme cannot break them all down, and the remaining half reach the nicotinic acetylcholine receptors on the postsynaptic side of the gap. Of course, all of this happens very quickly. Acetylcholinesterase can hydrolyze 4000 molecules of acetylcholine per site per second, so the half-life of the acetylcholine is estimated at 1 or 2 milliseconds. In fact, the distribution of the acetylcholinesterase perfectly matches that of the postsynaptic nicotinic receptors.

Thus, in the case of acetycholine, synaptic transmission is terminated chiefly by a biochemical reaction. In contrast, for catecholamines, the main mechanisms are diffusion of the neurotransmitter outside the synaptic gap and, primarily, its recapture by the presynaptic button.

Acetylcholine receptors are divided into two major families: nicotinic and muscarinic. The acetylcholine receptors in neuromuscular junctions are nicotinic. They consist of pentameric proteins that form an ion channel embedded in a lipid bilayer in the postsynaptic membrane. These receptors number nearly 10 000/µm². The acetylcholine binds to the extracellular part of the two alpha subunits of this channel protein, which has 5 subunits in all.

Each subunit in turn consists of four helicoidal transmembrane domains, designated M1 to M4. It is the M2 domains of the five subunits that together form the wall of the ion channel. This ion channel, which is opened by the allosteric conformation change triggered by the binding of the acetylcholine, is equally permeable to sodium and potassium. Its permeability to calcium accounts for only 2.5% of its total permeability. The half-life of adult nicotinic receptors is 4 to 6 days.