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large, it actually represents a small fraction of the total membrane protein. This partly

explains why receptor proteins are sometimes difficult to purify. From knowledge of

receptor numbers and theKdvalues for the agonist, it is possible to calculate the

occupancy of these receptors under normal physiological concentrations of the agon-

ist. In turn it is possible to calculate how the occupancy and the associated cellular

response will respond to changes in the circulating concentration of the agonist. The

percentage response change will be greater the lower the normal occupancy of the

receptors. This is seen from the shape of the dose–response curve within the physio-

logical range of the agonist concentration. It is clear that if the normal occupancy is

high, the response to change in agonist concentration is small. Under such conditions,

the response is likely to be larger if the receptor–agonist binding is a positively

cooperative process.

Receptor subclasses

Binding studies using both agonists and inverse agonists have identified receptor

subclasses for a given endogenous agonist. As an example, over a dozen types of

5-hydroxytryptamine (5-HT, serotonin) receptor have been identified (Table 17.1). An

interesting feature of some receptor subclasses is that not only do they have different

binding characteristics, but they may also trigger opposing cellular responses. Thus

there are three subclasses (b 1 ,b 2 andb 3 )ofb-adrenergic receptors with different

amino acid composition, affinities for agonists and physiological responses but all of

which are activated by adrenaline and noradrenaline.b 1 -Adrenergic receptors medi-

ate cardiac responses,b 2 -adrenergic receptors are involved in skeletal and smooth

muscle function, andb 3 -adrenergic receptors are involved in metabolic responses.

Selective synthetic agonists, such as salbutamol used in the treatment of asthma,

readily discriminate between the three subclasses.

Table 17.1G-protein coupling of 5-hydroxtryptamine (serotonin)

receptors

Family G-protein coupling Response

5-HT 1 (5 isoforms) Gi/Gocoupled Decreasing levels of cAMP

5-HT 2 (3 isoforms) Gq/G 11 coupled Increasing cellular levels of IP 3 and DAG

5-HT 3 (not GPCR) Ligand-gated Naþand Kþ

cation channel

Depolarising plasma membrane

5-HT 4 Gscoupled Increasing levels of cAMP

5-HT5A Gi/Gocoupled? Inhibition of adenylyl cyclase

5-HT 6 Gscoupled Stimulates adenylyl cyclase

5-HT 7 Gscoupled Increasing levels of cAMP

677 17.2 Quantitative aspects of receptor–ligand binding