Nerve and Muscle Physiology — Action Potential, Neuromuscular Junction and Muscle Contraction

An action potential is a rapid, stereotyped sequence of changes in the voltage across a membrane. The membrane voltage at any instant depends on the ratio of each ion inside to outside and on how permeable the membrane is to it. In neurons the rapid upstroke, depolarization, is an all-or-none event started by opening of voltage-gated sodium channels (Nav). The return to the resting value, repolarization, is carried by voltage-gated potassium channels (Kv). The Na+/K+-ATPase then restores the ionic balance over time.

Once the membrane reaches threshold, Na+ entry opens further Nav channels in a positive-feedback loop, so the response is the same size whatever the stimulus strength above threshold: that is the all-or-none behaviour. Voltage-gated channels have four domains around a central pore, each with six transmembrane helices. The positively charged S4 helix moves when the cell depolarizes and opens the pore. Sodium channels then undergo fast inactivation: a linker between domains III and IV plugs the pore, so the channel is open in structure but passes no ions.

This inactivation produces the absolute refractory period: while Nav are inactivated they cannot be recruited to fire another action potential. After the membrane repolarizes below threshold, the channels must pass through a deactivated state before they can reopen. The maximum firing rate of a neuron is therefore set by the kinetics of Nav inactivation and deactivation.

In an unmyelinated axon the depolarization has to spread to the adjacent membrane step by step. Myelin is a lipid-rich sheath that insulates the axon, with bare gaps at the nodes of Ranvier. Current flows quickly through the insulated cytoplasm to the next node, where Nav are clustered and the membrane is depolarized above threshold again. This node-to-node jumping is saltatory conduction and can increase conduction velocity by more than an order of magnitude compared with unmyelinated axons.

Nerve fibres are classified by diameter and conduction velocity, either by the Erlanger-Gasser letters (A to C) or by the numerical I to IV scheme. From A to C the fibres become smaller in diameter, less myelinated and slower.

The neuromuscular junction (NMJ) is a specialised synapse between a motor neuron and a skeletal muscle fibre. The motor neuron arises from the anterior horn of the spinal cord (or from brainstem nuclei for cranial nerves). On reaching the muscle it loses its myelin and divides into about 100 to 200 terminal ends. The transmitter is acetylcholine (ACh), made from choline and acetyl-CoA by choline acetyltransferase and stored in vesicles of roughly 5,000 to 10,000 molecules each, docked at active zones.

1. An action potential reaches the nerve terminal and opens voltage-gated Ca2+ channels.
2. Ca2+ binds synaptotagmin, which interacts with SNARE proteins (syntaxin and SNAP-25 on the membrane, synaptobrevin on the vesicle) and triggers vesicle fusion and ACh exocytosis.
3. ACh crosses the synaptic cleft (about 50 nm) and binds nicotinic receptors (ligand-gated ion channels) on the folded motor end plate.
4. Na+ enters and the end plate depolarizes from about -90 mV to -40 mV: the end-plate potential (EPP). One EPP is enough to reach threshold and fire a muscle action potential.
5. Acetylcholinesterase in the cleft breaks ACh down rapidly, so stimulation is brief; the breakdown products are recycled into the terminal.

Excitation-contraction coupling converts the muscle action potential into contraction. The action potential travels into the T-tubules, invaginations of the sarcolemma. Dihydropyridine receptors (DHPR) in the T-tubule membrane sense the depolarization and change shape; they are mechanically coupled to ryanodine receptors on the terminal cisternae of the sarcoplasmic reticulum, which open and release Ca2+. Ca2+ binds troponin C, moving tropomyosin off the myosin-binding sites on actin so cross-bridges can form.

In the cross-bridge cycle the starting state is rigor, with myosin tightly bound to actin and no ATP attached. ATP binds the myosin head and lowers its affinity for actin, so myosin detaches and cocks. ATP is hydrolysed to ADP + Pi, which stay on the head. The cocked head binds a new site on actin and the power stroke pulls the thin filament, provided Ca2+ remains on troponin C. Finally ADP is released and the head returns to rigor. Without ATP, as after death, rigor is permanent: this is rigor mortis.

A skeletal muscle fibre is multinucleated, with nuclei at the periphery, and is packed with myofibrils made of repeating sarcomeres, the fundamental contractile unit. Z lines bound each sarcomere. The A band in the centre contains the thick filaments (which may overlap thin filaments); within it the H zone has no thin filaments and the M line bisects it. The I bands lie on either side of the A band and contain thin filaments and the Z line.

• Length-tension: active tension is proportional to the number of cross-bridges and is highest at the optimum overlap of myosin and actin. When the muscle is shorter, filaments crowd and tension falls; when it is longer, less overlap means fewer cross-bridges. Total tension = active + passive tension.
• Force-velocity: as afterload rises, shortening velocity falls; maximal velocity occurs at zero afterload.
• Concentric contraction: force exceeds resistance and the muscle shortens. Eccentric contraction: resistance exceeds force and the muscle lengthens.
• Twitch and summation: one action potential gives one twitch. Because a twitch outlasts the action potential, a repeat stimulus before relaxation finds Ca2+ still high, so forces add; sustained fused contraction (called tetany in StatPearls, tetanus in most physiology texts) results.

Muscle fibres are classed by histological appearance, speed of contraction and resistance to fatigue. Type I (slow-twitch) fibres are generally thinner, have a denser capillary network and look red because of abundant myoglobin; they are fatigue-resistant and rely on oxidative metabolism. Type II (fast-twitch; IIa and IIb) fibres differ in oxidative enzymes, myoglobin and glycogen content, rate of force development, capillary density and fatigability, and also express different contractile and regulatory protein isoforms.

A single motor neuron and the fibres it supplies form a motor unit. The number of fibres per unit varies with muscle function: muscles of facial expression have far fewer fibres per motor unit than muscles used for gross activity such as swimming.

At the bedside, repetitive nerve stimulation shows a decremental response in postsynaptic disorders such as myasthenia, and an incremental response in Lambert-Eaton. Single-fibre EMG is the most sensitive test; increased jitter (variation in timing between two fibres of one motor unit) or blocking indicates a transmission defect. Muscle strength is graded on the MRC scale 0 to 5: 0 no contraction, 1 flicker only, 2 movement with gravity eliminated, 3 against gravity, 4 against gravity and some resistance, 5 normal.

• Na+ channels cause the upstroke, K+ channels the downstroke. Reverse statements are wrong.
• Absolute refractory period = Nav inactivated; it limits maximum firing rate.
• Myelinated fibres conduct faster by saltatory conduction; A to C means decreasing diameter and speed.
• Spindle Ia and tendon-organ Ib fibres are both A-alpha (group I); group II is A-beta; group III is A-delta; group IV is C.
• Troponin C binds Ca2+; troponin I inhibits; troponin T binds tropomyosin.
• ATP is needed for detachment, not for attachment of myosin to actin; no ATP means rigor.
• Relaxation is active: SERCA pumps Ca2+ back into the SR using ATP.