As previously discussed (see Chapter 19 ‘Pharmacodynamics: how drugs elicit a physiological effect’, p. 139), proteins span the cell membrane and can affect the rate of flow or direction of ions. These proteins are of two main types:

Both play in important role in conduction of a nerve impulse and muscle contraction.

Production of an Action Potential

Normally:

• The potassium concentration inside a cell is higher than the potassium concentration outside the cell.

• The sodium concentration outside the cell is higher than the sodium concentration inside the cell.

The sodium–potassium pump (Figure 31.1) is a form of active transport as both the sodium and potassium are moving against a gradient. It is responsible for maintaining an electrical balance across a cell membrane. The sodium–potassium pump actively pushes sodium molecules out of the cell and pumps potassium molecules in against a gradient. With each cycle, three Na⁺ ions are pumped out and two K⁺ ions are pumped in. The net result, as there are also negative ions such as Cl⁻ (chlorine) present both inside and outside the cell, is a net negative charge inside the cell and a positive charge outside the cell. This means that there is a potential difference across the cell membrane, known as the resting potential. To produce an action potential (Figure 31.2):

(i) The normal resting potential of a cell membrane is −60 to −70 mV, which means the inside of the cell is 60 to 70 mV less than the outside. If the membrane of the cell suddenly becomes more permeable to the ions then this situation will change. Permeability to ions is selective and occurs through ion channels, which will only permit certain ions to pass through them. Once the channel is open, the ion will pass either in or out of the cell down the concentration gradient. This dramatically changes the potential across the cell membrane.

(ii) In a nerve or muscle cell, if the ion channel for sodium is opened the sodium floods into the cell down the concentration gradient, taking its positive charge with it. The potential difference across the membrane now becomes positive. In other words, the inside of the cell becomes more positive than the outside. This is the depolarization phase. When the membrane reaches a certain threshold level, the nerve cell fires or the muscle cell contracts; if this threshold level is not reached, the nerve cell will not fire and the muscle cell will not contract. The size of the action potential (the spike in Figure 31.2) that is produced when the threshold level is reached is fixed; the action potential always fires at this size. This is the all-or-none principle.

(iii) When the action potential has been produced, the sodium gates start to close and the potential difference across the membrane opens the potassium gates, which allow potassium to flood out of the cell. This is the repolarization phase.

(iv) There is an overshoot, until the voltage across the membrane closes the potassium gate allowing the sodium–potassium pump to restore the balance once again (i). Blockage of these channels can be achieved by local anaesthetics (see Chapter 32 ‘Analgesia and relief of pain’, p. 254) and some anticonvulsant medication (Chapter 33 ‘Neurological disease’, p. 255).

Figure 31.1 The sodium–potassium pump mechanism. (i) Sodium pump before phosphorylation. (ii) Sodium pump after phosphorylation (which provides the energy for the pump); sodium moves into the gate. (iii) The gate opens and sodium moves out. (iv) Potassium moves in. (v) The gate closes. (vi) The concentrations of potassium and sodium are reversed temporarily until (i) is restored by normal movement down the concentration gradient.

Figure 31.2 The function of ion channels due to membrane potential (see text for explanation).

The action potential activates the voltage-gated calcium ion channels (channels opened by change in voltage across them) on the end of the axon at the synapse. The principle is very much the same as that for the sodium–potassium channel. Calcium enters the axon membranes, stimulating the release of the neurotransmitter acetylcholine into the neuromuscular synapse. This is taken up by the nicotinic receptors (see below) on the motor endplate. The sodium and potassium ion channels then open, allowing the sodium into the endplate and the potassium out. As the membrane is more permeable to sodium, the amount of sodium entering the cell is greater than the potassium leaving it, making the overall charge on the inside of the cell more positive. This action potential then spreads through the T-tubule network of the muscle fibres, ultimately releasing calcium ions from the endoplasmic reticulum in the muscle cells.

The actin filaments in the muscle cells are composed of three protein components:

Figure 31.3 illustrates the process of muscle contraction. In (i) and (ii), the released calcium ions interact with the troponin units, making them change shape and allowing the tropomyosin to slide out of its groove to expose the actin myosin-binding sites and allow the cross-bridge components of the myosin to interact with the actin (Figure 31.4). Figure 31.3(iii) shows how this interaction results in the head of the myosin tilting towards the arm and dragging the actin filament with it (the power stroke). At the end of this power stroke (iv) the myosin head is cocked back. Adenosine triphosphate (ATP) is released and binds to the myosin head, releasing it from the actin filament. The myosin head swings back ready to attach again and take another power stroke. In this way, the filaments are walked past one another, or ‘ratcheted’. The cross-bridges are reputed to work independently, each one attaching, pulling along and detaching in a continuous cycle.

Figure 31.3 The process of muscle contraction.

Figure 31.4 The action of the topomyosin–troponin complex: the myosin head to attaches to myosin binding sites on the actin filament.

As the action potential passes, the calcium ions are pumped back into the sarcoplasmic reticulum and, as the calcium is removed from the muscle fibres, the muscle relaxes. The theory is that, the greater number of cross-bridges that are attached at one time, the greater the force of contraction. All this is very energy dependent; the power source is ATP (see Figure 12.3, p. 91).