As the list of hormones and neurotransmitters grew at the end of the 19th century, the question followed how they act on sensitive tissues. Important progress in this matter came from two lines of research, one from the field of immunology, the other from physiology. Essential is the notion that cause and effect is the consequence of molecular interaction; the action of medicaments or hormones is a manifestation of their specific “affinity” for particular constituents of cells. In the words of Paul Ehrlich, “a component cannot act if it is not bound” and in the words of Langley, “the atropine or pilocarpine compounds are formed according to some law of which their relative mass and chemical affinity for the [receptive] substance are factors”.

Ehrlich grew up when Germany was at its zenith of colonial expansion, and confronted with nasty diseases in far-flung outposts. Chemically engineered textile dyes had just become a booming business in which multinationals such as Hoechst, AGFA (Gevaert) and BASF have their origins. Aniline, a product obtained from the distillation of coal-tar (creosol) and methyl-aniline (toluidine) where sought after compounds when, in 1856, William Henry Perkin had produced (in London) a purple colorant known under the name of Aniline Purple (and which was subsequently made fashionable by the French empress Eugenie). Ehrlich started his scientific career by exploiting these dyes in the staining of animal tissues and discovered the mast cell, rich in heparin containing granules that bind toluidine blue. He also developed an improved staining for the then freshly discovered tubercle bacillus (Mycobacterium Tuberculosis, Robert Koch in 1882) using aniline, fuchsine and gentian-violet. Dyes were also tested for “chemotherapy” purposes, such as trypan blue which owns its name due to its deleterious effect on Trypanosoma equinum (but, unfortunately, not on the human pathogens  brucei and cruzi). These were research contributions to the “colonial effort” of the nation.

Although it had occurred to Ehrlich that dyes must interact with specific cellular components it was only during his later studies on therapeutic sera (what we now call passive immunization), in particular dealing with a treatment for Diphtheria, that Paul Ehrlich elaborated the idea of “receptive side chains”. He reasoned that the sera must contain substances that first bind with and subsequently inactivate bacterial toxins. He assumed that the antipodes, toxins and receptive side chains, engage in a reversible chemical bond through the principle of “lock-and-key” (a metaphor just coined by the chemist Emil Fischer).

John Newport Langley, working in Cambridge, took over where Claude Bernard, professor in medicine at “College de France” in Paris, had left the stage, namely to sort out where exactly curare and nicotine acted in the stimulus response coupling between nerves and striated muscle? Bernard had made the crucial observation that when frog muscles are paralyzed by curare, they fail to respond to electric stimulation of the motor nerve but they still contract when the current is applied directly to muscle. Langley worked intermittently on the subject but made great strides in 1905 when he returned to the subject of nervous transmission in the context of the efferent somatic system (motor neurons). Langley measured contraction of the gastrocnemius muscle (in anaesthetized fowl) following injection of nicotine into the blood-stream. Upon injection of nicotine, and in the absence of motoneurons, the animals stretch their legs (and open their eyes) and this is undone by the subsequent injection of curare. Again, direct electric stimulation of the same muscle still leads to contraction. He concludes: ”it may be inferred that neither the poisons nor the nervous impulse act directly on the contractile substance of the muscle but on some accessory substance…. we may speak of it as the receptive substance”. Archibald Hill, an undergraduate student of Langley, provided essential mathematical evidence that the time course of contraction corresponds with the calculated rate of ligand binding to receptors (forming reversible “compounds”) and not with slow diffusion of nicotine into the muscle tissue.

Langley only gives a hint about a possible mode of action in 1908 by stating: “My theory of the action is in general in lines of Ehrlich’s theory of immunity. I take it that the contractile molecule has a number of “receptive” or “side-chain” radicles and that nicotine, by combining with one of these, causes contraction and, by combining with another, causes twitching…”. Whilst Langley refers to Ehrlich’s work, Ehrlich adopts Langley’s nomenclature when he writes in his Nobel speech in the same year: “tetanus toxin for instance, must unite with certain chemical groupings in the protoplasm of cells, particularly the motor ganglion cells, and that this chemical union represents the prerequisite and cause of the disease. I have therefore simply called such groupings “poison receptors” or just “receptors”.

The term “receptor” does not yet appear in the index of the 1955 edition of The Pharmacological Basis of Therapeutics, the standard American textbook of Pharmacology, but the following sentence was there: “Years ago, Langley named the differentiating substance the ‘receptive substance’; this term is still widely employed, but it must be realized that the ‘receptor’ may not be a morphologically demonstrable structure”. More importantly of course is that Langley’s concept of the receptive substance was taken up by others, notably Henry Dale and Otto Loewi with respect to chemical synaptic transmission. By 1970 the nicotinic acetylcholine receptor was purified from the electric organ of Torpedo. In that year Bernard Katz and Ricardo Miledi demonstrated that addition of acetylcholine was linked to changes in membrane conductance in single synapses. For more information how receptors came to light, read the “prologue” of the 3^rd edition of Signal Transduction below:

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Dr Kramer’s 3^rd edition of Signal Transduction is a reference on cellular signaling processes that provides a historical overview of how the concept of stimulus-response coupling arose in the early twentieth century and shaped our current understanding of the action of hormones, cytokines, neurotransmitters, growth factors and adhesion molecules.

Key Features:

• In-depth insight into a subject central to cell biology and fundamental to biomedicine, including the search for novel therapeutic interventions
• Essential signaling events embedded in rich physiological and pathological contexts
• Extensive conceptual color artwork to assist with comprehension of key topics
• Special emphasis on how molecular structure determines protein function and subcellular localization
• Employment of unambiguous protein names (symbols) in agreement with leading protein- and gene databases, allowing the learner to extend his/her exploration on the web
• Click here to find out more about the dedicated website.

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About the Author

IJsbrand Kramer (principal author) is a Professor at the University of Bordeaux, working in the European Institute of Chemistry and Biology (IECB). He holds a Bachelors and Masters degree in BioMedicine from the University of Utrecht, The Netherlands, with a one year research-excursion in the Department of Cell Biology at the University of Liverpool, UK. Most of his research centers on the theme of inflammation, starting with neutrophils and the NADPH oxidase, synovial fibroblasts and destruction of the joint and more recently podosomes formation and extracellular matrix destruction in vascular endothelium. He has been co-director of two European Programmes (Interbio and Transbio) that aimed at enhancing industrial innovation in the biomedical sector in the South West European Region (SUDOE).

References:

• Dr Kramer’s image: for book/publicity purposes, image of the author by © Maarten Kramer
• Ehrlich P. Croonian Lecture: on immunity with special reference to cell life. Proc R Soc Lond 1899;66:424-448.
• Hill AV. J Physiol 1909;39:361-373.The mode of action of nicotine and curari, determined by the form of the contraction curve and the method of temperature coefficients.
• Katz B, Miledi R. Membrane noise produced by acetylcholine. Nature 1970;226:962-963
• Langley JN. On the reaction of cells and of nerve endings to certain poisons chiefly as regards the reaction of striated muscle to nicotine and to curare. J Physiol 1905;33:374-413.
• Miledi R, Molinoff P, Potter LT. Isolation of the cholinergic receptor protein of Torpedo electric tissue. Nature 1971;229:554-557.