Elsevier

Neuropharmacology

Volume 39, Issue 4, 15 March 2000, Pages 523-546
Neuropharmacology

The concept of transmitter receptors: 100 years on

https://doi.org/10.1016/S0028-3908(99)00137-9Get rights and content

Abstract

It is nearly one hundred years since John Langley of Cambridge developed the idea of the ‘receptive substance’ or ‘receptors’ as we now call them. This historical review traces the background to his introduction of this concept of the transmitter receptor and of how succeeding generations built on his ideas to generalise the applicability of this concept to synapses in general. It starts with a consideration of the discovery by Bernard (1844) that curare could paralyse rabbits without affecting their hearts because, as Vulpian (1866) suggested, curare acts on some intermediate zone between nerve and muscle. No further progress could be made without establishing the idea of chemical transmission, which Elliott (1904) then achieved, building on observations concerning sympathetic transmission to smooth muscle made previously by his mentor Langley (1901). Then between 1905 and 1907 Langley, in a wonderful act of creative ability, carried out a series of experiments on the somatic neuromuscular junction which established the idea of transmitter receptors. This review gives details of the experiments which persuaded both Langley and a recalcitrant Ehrlich that pharmacological substances could possess the necessary structure for them to combine with appropriate molecules on cells. The subsequent identification by Dale and his colleagues (1936) of acetylcholine as the transmitter acting on the receptors first discovered by Langley at the somatic neuromuscular junction as well as of acetylcholine on receptors in the heart by Loewi (1921) is then detailed. The review concludes with the triumph of the first recordings of the electrical signs of single channel openings by Neher and Sakmann (1976) at the receptors which Langley had first described.

Introduction

The idea of the ‘receptive substance’, or receptors as we now call them, was developed by John Langley of Cambridge 90 years ago (Fig. 1A). Between 1901 and 1905 Langley laid the foundations for the idea of chemical transmission with his student Thomas Elliott (Fig. 1B) through their investigations on sympathetic neuroeffector transmission. In an extraordinary act of creative ability, Langley then carried out a series of investigations between 1905 and 1907 on the somatic neuromuscular junction that established the idea of transmitter receptors. This historical review traces the development of Langley's ideas over this period, especially in relation to the concept of the ‘chemoreceptor’ developed by Paul Ehrlich. The review then examines how this work was applied by a number of investigators to place the concept of transmitter substances and their receptors on a firm foundation for the modern molecular approaches to the delineation of receptor types and their function. In order to assist the reader, a chronological table of significant experiments in the history of receptors is provided (Table 1), together with a list of the major contributors to these experiments (Table 2) and the agents they used to delineate the receptor concept (Table 3).

Section snippets

Claude Bernard and curarization: the notion of an intermediate zone between nerve and muscle

In June of 1844 Claude Bernard wrote in his experimental note book that:

A poisoned arrow obtained from a friend who had connections with South American natives was thrust into the subcutaneous tissue of a rabbit at the internal part of the thigh and maintained there for 30 seconds. The animal was then observed. At first, nothing happened. But after six minutes it became totally paralysed: no reflex movements were observed on pinching the rabbit, although the heart continued to beat. The animal

Paul Ehrlich and the idea of the ‘receptive side chains’ of cells

In 1885, Ehrlich presented his thesis to the University of Leipzig in which he described for the first time his ‘side chain theory’ of cellular action. The protoplasm of a cell was considered to be a giant molecule incorporating a central structure responsible for the specific activity of a particular cell type (such as a muscle cell or a neurone), which possessed chemical side chains. The side chains were envisaged as carrying out processes common to all cells. For example, one such side chain

Langley and Elliott: the emergence of the concept of chemical transmission between sympathetic nerves and smooth muscle

In 1899 Lewandowsky observed that supra-renal extract in cats causes dilation of the pupil, withdrawal of the nictitating membrane (Fig. 3A), separation of the eyelids and protrusion of the eyeball. Lewandowsky suggested that the extract acted directly on the smooth muscle and not on the nerve endings in the muscle as he obtained the same results with the extract after excision of the superior cervical ganglion and degeneration of the postganglionic nerves as in the normal animal. This was an

The action of curare and John Langley's development of the idea of transmitter receptors

By 1904 it was clear that adrenaline acted on those smooth muscles that received a sympathetic innervation and that this action was independent of the nerve supply to the muscles. Elliott did not elaborate further on his concept of chemical transmission in his 1905 paper that there is a:

mechanism developed out of the muscle cell in response to its union with the synapsing sympathetic fibre, the function of which is to receive and transform the nervous impulse (Fig. 3F)

However, there were

The Langley–Ehrlich receptor theory

It is fascinating to trace the productive interaction of the ideas of Ehrlich and Langley over this period from 1878 to 1908, beginning as each did from quite different research programs. In the case of Ehrlich, his research was concerned with drug resistance as a consequence of studies on the chemotherapy of trypanosomes. The receptive side chain concept was developed in order to give a theoretical underpinning to his work on the chemotherapy of such micro-organisms, in particular in the use

The discovery of acetylcholine and its physiological action at autonomic neuroeffector junctions

In 1906 Hunt and Taveau synthesized acetylcholine and reported that:

as regards its effect upon the circulation, it is the most powerful substance known.

They went on to say:

we have not determined the cause of the fall of blood pressure from acetyl-cholin, but from the fact that it can be prevented entirely by atropine, I am inclined to think that it is due to an effect upon the terminations of the vagus in the heart.

In the same year, Dixon (1906) gave a description of his experiments on the

The physiological action of acetylcholine in autonomic ganglia

In 1934 experiments were also begun to see if acetylcholine could be detected at neuronal synapses in addition to neuroeffector junctions. To this end Feldberg and Vartiainen (1934) were able to show that:

when the superior cervical ganglion of the cat is perfused with warm, oxygenated Locke's solution containing a small proportion of eserine, acetylcholine appears in the venous effluent whenever the cervical sympathetic nerve is effectively stimulated, and only then.

The assay for this

The identity of acetylcholine as the transmitter substance at somatic neuromuscular junctions

Although the concept of the transmitter receptor was developed primarily in relation to striated muscle, as detailed above, identification of acetylcholine as the transmitter substance that acts on these receptors came relatively late, well after the establishment of acetylcholine as the transmitter from the vagus nerve to the heart. In the late 1920s and early 1930s, the problem of the relationship between motor nerves and muscle revolved around questions relating to their relative

The discovery of the physiological action of single acetylcholine receptors

The study of the physiological action of single acetylcholine receptors began in 1970 with the discovery by Katz and Miledi of membrane noise at the endplate in response to the steady action of acetylcholine from a micropipette. They hypothesised that during such a steady application:

the statistical effects of molecular bombardment might be discernible as an increase in membrane noise, superimposed on the maintained average depolarisation.

This is what in fact they observed with an intracellular

Conclusion

The saga of the concept of the receptor has been followed from its beginnings in the hands of Langley and Ehrlich to the triumph of recording the electrical signs of the opening of a single acetylcholine receptor channel. This work took almost exactly a century to accomplish, from the experiments of Langley in 1874 on pilocarpine and atropine to those of Neher and Sakmann (1976). The structure of the receptor molecule was also opened up by the discovery in the late 1960s by Lee and his

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