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, 147 Suppl 1 (Suppl 1), S9-16

The Receptor Concept: Pharmacology's Big Idea

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The Receptor Concept: Pharmacology's Big Idea

H P Rang. Br J Pharmacol.

Abstract

Chemical signalling is the main mechanism by which biological function is controlled at all levels, from the single cell to the whole organism. Chemical recognition is the function of receptors, which, in addition to recognising endogenous chemical signals, are also the target of many important experimental and therapeutic drugs. Receptors, therefore, lie at the heart of pharmacology. This article describes the way in which the receptor concept originated early in the 20th century, and evolved through a highly innovative stage of quantitative theory based on chemical kinetics, to the point where receptors were first isolated and later cloned, until we now have a virtually complete catalogue of all the receptors present in the genome. Studies on signal transduction are revealing great complexity in the events linking ligand binding to the physiological or therapeutic response. Though some simple quantitative rules of 'receptor theory' are still useful, the current emphasis is on unravelling the pathways that link receptors to responses, and it will be some time before we know enough about them to embark on the next phase of 'receptor theory'.

Figures

Figure 1
Figure 1
A.J. Clark's early contributions to the receptor concept. (a) Concentration–effect curves for acetylcholine on (A) frog heart, (B) frog rectus abdominis muscle. Continuous curves fitted to the Hill–Langmuir equation (from Clark, 1926a, 1933). (b) Antagonism of acetylcholine by atropine on frog heart. Ordinate: % inhibition of contraction (y), plotted as log10[y/(100−y)]. Abscissa: Acetylcholine concentration (log10M). Successive lines (I–VII) represent atropine concentrations from zero to 10−3M (from Clark, 1926b).
Figure 2
Figure 2
Concentration–effect curves for a series of alkyl trimethylammonium compounds on guinea-pig ileum (from Stephenson, 1956).
Figure 3
Figure 3
Hypothetical models of receptor activation by agonists (see text). (a) Graded activation model, (b) Simple 2-state model, (c) Reversible 2-state model, (d) Ternary complex model. The ternary complex model (d) includes complex formation between the receptor (R) and a G-protein (G).
Figure 4
Figure 4
Early studies of receptor binding. (a) Autoradiographic image of [14-C] calabash curarine to endplate regions of mouse diaphragm (from Waser, 1960). (b) [3H]-Atropine binding to longitudinal muscle of guinea-pig ileum. Analysis of the full binding curve revealed two saturable binding sites, plus a linear component. Binding site 1 represents binding to muscarinic ACh receptors (from Paton & Rang, 1965).

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