Signal Transduction
Eserine or physostigmine, an alkaloid isolated
from the Calabar bean, had previously shown by Loewi to be an acetylcholinesterase inhibitor.
John Eccles, awarded the Nobel Prize together with Andrew Huxley and Alan Hodgkin in 1963 for discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane.
The structures of atropine and pilocarpine are shown in Figure 3.4, page 47.
denervated muscles. There were still a number of real problems to be overcome. Chief among these was the transient nature of the pulse of neurotransmitter. Also, it was not sufficient to show that acetylcholine applied from a pipette was capable of inducing a response. To prove its role in neurotransmission it still remained necessary to demonstrate its presence in the relevant presynaptic nerve endings and then to show that it is released upon electrical stimulation.
Feldberg describes his introduction of eserine and the use of an eserinized leech muscle preparation as a specific and sensitive device for measuring the acetylcholine present in the various effluents (blood, perfusate, etc.). This was the key that opened the way to the eventual conversion of that most obdurate sceptic, the electrophysiologist John Eccles. Even so, without naming any names, Zenon Bacq49 reports that even as late as 1950, certain
eminent physiologists were still refusing to incorporate the theory of chemical transmission into their teaching.
Receptors and ligands
Among the numerous proteins inserted in the plasma membranes of cells are the receptors. These possess sites, accessible to the extracellular milieu, that bind, with specificity, soluble molecules often referred to as ligands. The binding of just a few ligand molecules may then bring about remarkable changes within the cell as it becomes ‘activated’or ‘triggered’. Although our knowledge of these interactions is quite extensive, it is not so very long ago that the very notion of a receptor was merely conceptual, indicating the propensity of a cell or tissue to respond in a defined manner to the presence of a hormone or other ligand. Nowadays, the receptors are familiar to us as products of the molecular biology revolution. They can be synthesized in the laboratory in milligram quantities as recombinant proteins; they can be modified by point mutations, deletions, or insertions, and by the formation of chimeric structures. They can be expressed in the membranes of cells from which they are normally absent.
The concept of a specific binding site for a ligand certainly predates the discovery of the first hormones and can be ascribed to John Newport Langley.54 Based on the mutual antagonism of the poisons atropine and pilocarpine (later found to be active at muscarinic cholinergic receptors), he proposed that these substances form ‘compounds’ in their target tissues to an extent based on the rules of mass action.
I think it is quite clear that if either atropin or pilocarpin is present in the blood of the sub-maxillary gland, then either pilocarpin or atropin
respectively is able in sufficient quantity to produce the effects it produces when present alone in certain other quantity.
The greater the quantity of atropin the greater is this certain other quantity of pilocarpin; when a large quantity of pilocarpin overcomes
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Prologue: Signal Transduction, Origins and Ancestors
the correspondingly large quantity of atropin it restores the effect of the secretory fibres less, and causes less secretion than when a smaller dose of pilocarpin overcomes a still paralysing but smaller dose of atropin.
Until some definite conclusion as to the point of action of the poisons is arrived at it is not worth while to theorise much on their mode of action; but we may, I think, without much rashness, assume that there is some substance or substances in the nerve endings or gland cells with which both atropin and pilocarpin are capable of forming compounds. On this assumption then the atropin and the pilocarpin compounds are formed according to some law of which their relative mass and chemical affinity for the substances are factors.
Langley was careful to acknowledge the work of others, particularly Luchsinger who had already described the antagonistic actions of atropine and pilocarpine on the sweat glands of the foot of the cat in almost graphic terms:
there exists between pilocarpin and atropin a true mutual antagonism, their actions summing themselves algebraically like wave crests and hollows, like plus and minus. The final result depends simply and solely upon the relative number of molecules of the poisons present.
Twenty-eight years later, in his Croonian lecture of 1906, Langley stated:
Since neither curari nor nicotine, even in large doses, prevents direct stimulation of muscle from causing contraction, it is obvious that the muscle substance which combines with nicotine or curari is not identical with the substance which contracts. It is convenient to have a term for the specially excitable constituent, and I have called it the receptive substance. It receives the stimulus and, by transmitting it, causes contraction . . . The mutual antagonism of nicotine and curari on muscle can only satisfactorily be explained by supposing that both combine with the same radicle of the muscle, so that nicotine-muscle compounds and curari-muscle compounds are formed. Which compound is formed depends on the mass of each poison present and the relative chemical affinities for the muscle radicle.
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