Nerve conduction

Conduction of impulses through nerves occurs as an all-or-none event called the action potential. The action potential is caused by voltage-dependent opening of sodium and potassium channels in the cell membrane.

The sodium equilibrium potential (Eq Na⁺) is +  60   mV and the potassium equilibrium potential (Eq   K⁺) is −  90   mV. Since a resting nerve has 50–75 more potassium channels open than sodium channels, the resting membrane potential is −  70   mV.

Figure 4.1 shows the concentrations of sodium and potassium inside and outside a resting nerve. The Na⁺/K⁺ pump (Na⁺/K⁺ ATPase) is an energy-dependent pump that functions to maintain the concentration gradient of these two ionic species across the membrane. Three sodium ions are pumped out of the cell for every two potassium ions pumped in, and thus the excitability of the cell is retained. Figures 4.2 and 4.3 summarize the events that occur during a nerve action potential. During a nerve action potential:

Fig. 4.1 Intracellular and extracellular sodium and potassium concentrations. The Na⁺/K⁺ pump maintains these concentration gradients across the cell membrane.

Fig. 4.2 Nerve action potential. For explanation of points 1–6, see Figure 4.3.

Fig. 4.3 State of sodium and potassium channels and membrane potential at different stages of the neuronal action potential

Figure 4.4 shows the voltage-operated sodium channels in their inactivated, activated and resting states. Two types of gate exist within the channel; the m-gates and the h-gates. These gates are open or closed according to the state of the channel.

Fig. 4.4 Voltage-operated sodium channels in their inactivated, activated and resting states. The m-gates and h-gates open or close according to the state of the channel.

In the resting sodium channel, the m-gates are held closed by the strongly negative (−  70   mV) electrical gradient across the membrane. Once an action potential begins to propagate, the loss of the membrane potential causes the m-gates to open, allowing sodium into the cell, further propagating the action potential. After a very short time, a further conformational change causes the h-gates to close, inactivating the sodium channel. The membrane then re-polarizes, and once at −  70   mV the m-gates again close, and the h-gates open so the sodium channel is back in its resting state.

Somatic nervous system

Neuromuscular junction

Physiology of transduction

Skeletal (voluntary) muscle is innervated by motor neurons, the axons of which are able to propagate action potentials at high velocities. The area of muscle that lies below the axon terminal is known as the motor end-plate, and the chemical synapse between the two is known as the neuromuscular junction (NMJ).

The axon terminal incorporates membrane-bound vesicles containing the neurotransmitter acetylcholine (ACh). Depolarization of the presynaptic terminal of the nerve by an action potential (generated by sodium influx) causes voltage-sensitive calcium channels to open, allowing calcium ions into the terminal. Normally, the level of calcium ions inside the nerves is very low, much lower relative to the external concentration. This calcium influx results in the release of ACh by exocytosis from vesicles. ACh diffuses across to the muscle membrane where it binds to the nicotinic acetylcholine receptor (nicAChR) and/or is inactivated by acetylcholinesterase (Fig. 4.5). Several events then occur:

• During association, ACh binds to the nicAChR, which is an ion channel that allows cations into the muscle (mainly sodium but also potassium to a lesser extent).

• During the conformational change, the pore of the ion channel is open for 1   ms, during which approximately 20   000 sodium ions enter the cell. The resulting depolarization, called an end-plate potential (EPP), depolarizes the adjacent muscle fibre.

• If the cellular response is large enough, an action potential is generated in the rest of the muscle fibre (sodium influx), resulting in the opening of voltage-operated calcium channels, but this time the calcium influx mediates contraction.

• ACh is rapidly inactivated by an enzyme called acetylcholinesterase (AChE) which hydrolyses ACh into the inactive metabolites choline and acetic acid.

• In the synthesis of ACh, the choline generated is taken up by the nerve terminal where another enzyme, choline acetyl transferase (ChAT), converts it back to ACh to be reused.

Fig. 4.5 Physiology of impulse transduction at the neuromuscular junction (NMJ) showing the site of action of drugs used in conjunction with the NMJ. (ChAT, choline acetyltransferase; vesamicol, an experimental drug; VOCC, voltage-operated calcium channel; AChE, acetylcholinesterase; VOSC, voltage-operated sodium channel.)

Hints and Tips

The neuromuscular junction is a very important site for therapeutic manipulation. The electrical impulse from the neuron is converted into a chemical signal that mediates the effect – largely muscular contraction.

Nicotinic acetylcholine receptor

The nicAChR is made up of five subunits (two α, one β, one γ and one γ) that traverse the membrane and surround a central pore. All the subunits show high sequence identity. The binding site for ACh lies on the α subunits, therefore ACh must bind to both α subunits to open the channel.

Each subunit has four membrane-spanning regions (helices), i.e. each receptor has a total of 20 regions. One of the transmembrane helices (M₂) from each subunit forms the lining of the channel pore.

Pharmacological targets

There are three major targets within the NMJ for clinically useful drugs (Fig. 4.6):

• Presynaptic release

• Nicotinic acetylcholine receptor

• Acetylcholinesterase.

Fig. 4.6 Targets for clinically useful drugs at the neuromuscular junction

Drugs affecting the neuromuscular junction

Presynaptic agents

Drugs inhibiting ACh synthesis

The rate-limiting step in the synthesis of ACh is the uptake of choline into the nerve terminal.

Hemicholinium is an analogue of choline that competitively blocks the choline transporter and causes a depletion of ACh stores. Because of the time taken for the stores to run down, the onset of this drug is slow. This, and the frequency-dependent nature of the block (depletion of stores is related to release of ACh), means that it is not useful clinically. The block is reversed by the addition of choline.

Drugs inhibiting vesicular packaging of ACh

Vesamicol inhibits the active transport of ACh into storage vesicles and results in neuromuscular block.

Drugs inhibiting ACh release

Calcium entry into the nerve terminal is necessary for the release of ACh; thus, agents such as aminoglycoside antibiotics (e.g. streptomycin) that prevent this step will cause neuromuscular blockade. Muscle paralysis is occasionally a side-effect of aminoglycoside antibiotics, but it can be reversed by the administration of calcium salts.

Botulinum toxin is a neurotoxin produced by the anaerobic bacillus Clostridium botulinum. The toxin is very potent and it is believed to inhibit ACh release by inactivating actin, which is necessary for exocytosis. In botulism, a serious type of food poisoning caused by this toxin, victims experience progressive parasympathetic and motor paralysis. Botulinum toxin type A is sometimes used clinically in the treatment of excessive muscle contraction disorders (dystonias) such as strabismus (squint), spasticity and tremors. More often, however, it is used cosmetically to diminish the appearance of wrinkles.

β-Bungarotoxin contained in snake venom acts in a similar manner to botulinum toxin.

Postsynaptic agents

Non-depolarizing blockers

These act as competitive antagonists by binding to the nicAChR but not activating it, and producing motor paralysis. Details of the most commonly used non-depolarizing blockers are given in Figure 4.7

Fig. 4.7 Non-depolarizing blockers of postsynaptic receptors at the neuromuscular junction

Approximately 80–90% of receptors must be blocked to prevent transmission, since the amount of ACh released by nerve terminal depolarization usually greatly exceeds that required to generate an action potential in the muscle. The drugs are all quaternary ammonium compounds and, therefore, do not cross the blood–brain barrier or the placenta. They are poorly absorbed orally and must be administered by intravenous injection. ‘Tetanic fade’ (i.e. non-maintained muscle tension during brief nerve stimulation) is seen with some of these drugs. This is due to the blocking of presynaptic autoreceptors which usually maintain the release of ACh during repeated stimulation.

The block can be reversed by anticholinesterases and depolarizing drugs. It is also enhanced in patients with myasthenia gravis. The main side-effect from these drugs is hypotension caused by the blocking of ganglionic transmission. Histamine release from mast cells, resulting in bronchospasm, may be a problem in certain individuals.

Depolarizing (non-competitive) blockers

Depolarizing blockers initially activate receptors, causing depolarization, but in doing so block further activation.

Depolarizing blockers act on the motor end-plate in the same manner as ACh, i.e. they are agonists and increase the cation permeability of the end-plate. However, unlike ACh, which is released in brief spurts and rapidly hydrolysed, depolarizing blockers remain associated with the receptors long enough to cause a sustained depolarization and a resulting loss of electrical excitability (phase I).

Repeated or continuous administration of depolarizing blockers leads to the block becoming more characteristic of non-depolarizing drugs. This is known as phase II and is probably due to receptor desensitization, whereby the end-plate becomes less sensitive to ACh. The block starts to show and it is partly reversed by anticholinesterase drugs.

Suxamethonium is the only depolarizing blocker used clinically because of its rapid onset time and short duration of action (approximately 4 mins). It must be given by intravenous injection. It is rapidly hydrolysed by plasma cholinesterase, although certain people with a genetic variant of this enzyme may experience a neuromuscular block that may last for hours.

Depolarizing blockers have no effect in patients with myasthenia gravis, since these patients have a decreased number of receptors at the end-plate. In this instance, the blocking potency of depolarizing blockers is reduced.

The side-effects of depolarizing blockers include:

• Initial spasms, which occur prior to paralysis, often resulting in postoperative muscle pain.

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