The simplest way to consider the action of a chemical on an enzyme or receptor is the concept of the ‘lock and key.’ A bond is made with the enzyme or receptor (Figure 19.1). If the protein is an enzyme, a chemical reaction will take place; if it is a receptor, it might trigger a chemical reaction or start a chain of events leading to a physiological response.

Figure 19.1 The ‘lock and key’ mechanism.

This is a very simplistic explanation and there might be a certain moulding of the site to the substrate or ligand, as the protein structure is not completely immobile, but generally speaking the ‘lock and key’ mechanism is a reasonable concept.

Receptors are specialized areas in cell walls that interact with molecules (ligands). Ligands can be hormones, neurotransmitters or drugs or chemicals from remedies and are found in:

Receptors work in a similar way to enzymes with regard to the attachment of chemicals to the receptor sites. In many cases, the receptors are linked up to intermediary systems such as G proteins (Figure 19.5, p. 141).

This time, however, the attachment of a molecule will activate the site, producing a physiological effect through a series of chemical reactions (agonist) [Figure 19.4(i)] or block the site and therefore the active response of the cell to the chemical (antagonist) [Figure 19.4(ii)].

Figure 19.4 Action of receptors.

Some drugs can have a dual action, simultaneously behaving as an agonist for one receptor and an antagonist to another, e.g. buprenorphine (see Chapter 32 ‘Analgesia and relief of pain’, p. 252).

Receptors are effectively sensors for the chemical communicating system in the body, which coordinates the function of all the different cells in the body.

Agonists

These molecules can activate a site by binding to it. Many hormones and neurotransmitters work in this way. They will either work directly as in the case of ion channels (see Figure 19.6) or through an intermediary (transduction), for example a G protein (Figure 19.5). The response from the stimulated cell can lead to:

• enzyme activation or inhibition

• ion channel modulation

• DNA transcription.

Figure 19.5 The action of G protein. (i) A hormone or neurotransmitter attaches itself to a cell membrane or synaptic receptor. The receptor is composed of a protein embedded in the phospholipid membrane that straddles the membrane. (ii) This changes the shape of receptor site of the receptor protein inside the cell. (iii) The G protein moves laterally along the membrane and binds to the now activated receptor site. (iv) This triggers an exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP). (v) The G protein moves laterally to the inactive enzyme, releasing a phosphate into a receptor site, activating the receptor site of the enzyme ready for the substrate. (vi) The substrate attaches. Once the reaction has taken place the enzyme loses the phosphate molecule.

Ion Channels

Ion channels are composed of protein and control the flow of ions in and out of cells (Figure 19.6; see Chapter 16 ‘How do drugs get into cells?’, p. 124 and Figure 31.2, p. 237). They differ according to:

• the type of ion they allow through (e.g. Na⁺, K⁺, Cl⁻)

• the way they are regulated

• their structure.

Figure 19.6 An ion channel.

There are several kinds:

• Non-gated (resting channels): continuously open, allowing a leakage of ions.

• Chemically gated:

• Direct: the drug directly binds to parts of the channel protein. This might amount to a simple physical blocking of the channel by the drug molecule. Local anaesthetics can work in this way, blocking the sodium–potassium gate.

• Indirect: activated by a G protein and other intermediaries.

• Ligand gated: linked directly to a receptor and opened only when the receptor is occupied by an agonist.

• Voltage gated: see Figure 31.2 (p. 237). The gate is controlled by a voltage sensor, which opens or closes the gate according to the level of the membrane potential.

Ions and small molecules need to be transported across the lipid membranes of cell walls (Figure 19.7(i)). The carrier is a protein, which has a recognition site that makes specific for particular substrates. These can be blocked [Figure 19.7 (ii)] or made to take a false substrate, which then accumulates in the cell [Figure 19.7 (iii)] and affects the cell metabolism in some way.

Figure 19.7 Carrier systems and how they can be affected by drugs.

The physiological processes of the body are controlled by feedback loops. The presence or absence of a substance in the body is fed back into the system that produces it, turning production on or off to maintain the correct level of that substance in the body.

The endocrine system is an example of a feedback loop system. It comprises a group of glands situated at various locations around the body, that secrete chemical messengers (hormones), which circulate in the bloodstream to affect distant organs or other glands. A classic feedback loop occurs within the female reproductive system to produce the menstrual cycle and the induction and shutdown of labour (see Figure 38.1, p. 300).

See Chapter 40 ‘Toxicology’ p. 317.