Receptive Substance Research Articles

Don’t Flip Out: AChRs are Primed to Catch and Hold Your Attention

The muscle nicotinic receptor has come a long way since Langley doused it with nicotine and curare, dubbing it “the receptive substance”, more than a century ago (1). Neher and Sakmann did the first biological single-molecule experiments on those same channels (2), and similar work continues to expose mechanisms that underlie Langley’s observations.

Introduction to the series on novel aspects of cardiovascular G-protein-coupled receptor signaling.

The initial concept of drugs acting on receptors is generally credited to John Newport Langley (1852–1925) and his pioneering work on the antagonistic effects of atropine,1 and to Paul Ehrlich (1854–1915), who coined the word “receptor.”2 It was in 1905 that Langley (together with the much forgotten Thomas Renton Elliott) proposed that a “receptive substance” was the site of action of chemical mediators liberated by nerve stimulation.3 At approximately the same time, Ehrlich in his studies on immunity postulated that a drug could have a therapeutic effect only if it “unites with certain chemical groupings in the protoplasm of cells” and called such cell groupings “poison receptors” or just “receptors.”2 In experiments performed in the early 1900s, the English pharmacologist and neurophysiologist Sir Henry Hallett Dale (1875–1968) identified the muscarinic and cholinergic actions of acetylcholine and subsequently shared with Otto Loewi the Nobel Prize in 1936 for discoveries relating to the role of acetylcholine in the chemical transmission of nerve impulses.4 Dale coined the terms “adrenergic” and “cholinergic” to describe the actions of autonomic and motor nerve fibers, and he recognized that the sympathetic myoneural junction could also be called “the receptive mechanism for adrenaline.”5 Based on Dale's experiments on the physiological effect of Ergot preparations, the concept evolved that there were two classes of adrenotropic receptors: those whose action results in excitation and those whose action results in inhibition of the effector cells.5,3 This concept of two classes of adrenotropic receptors was further clarified by Raymond Ahlquist at the Medical College of Georgia, when in 1948 he published his work showing that it is an oversimplification to classify adrenotropic receptors as either excitatory or inhibitory.6 By studying the relative potencies of six sympathomimetic amines on several isolated mammalian preparations, …

Historical evolution of the neurotransmission concept

In this review we analyse the evolution of the neurotransmission phenomenon, whose nature have had three basic historical interpretations; a first, of an humoral nature, formulated by the classical Greeks (Alexandrian School), and which lasted, thanks to the work of Galen, until the sixteenth century (the theory of spiritus animalis); a second, purely mechanical one, developed on the basis of Cartesian conceptions, and which dominated in the seventeenth and eighteenth centuries; and finally, the electrochemical interpretation, which emerged in the nineteenth century, coinciding with the coming of age of numerous scientific disciplines, such as microscopic anatomy (Cajal), physiology (Sherrington), pharmacology (Bernard, Schmiedeberg) or experimental chemistry (Hensing). This latest interpretation can be broken down into an electrical hypothesis, dominant in the nineteenth century (Galvani, Du Bois-Reymond), and the current chemical hypothesis, which can be dated back to 1904, thanks to the research and the research by Elliott (chemical mediators) and Langley (receptive substances) on sympathetic stimulation. Finally, we describe the process of the discovery of the different neurotransmitters and neuroreceptors, and analyse the new interpretations postulated in relation to the neurotransmission concept at the dawn of the twenty-first century.

Mammalian nicotinic acetylcholine receptors: from structure to function.

The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a "receptive substance," from which the idea of a "receptor" came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of alpha-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer's, Parkinson's, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.

Drug discovery paradigms: past, present, future – a centennial symposium of the American Society for Pharmacology and Experimental Therapeutics

Background: The American Society for Pharmacology and Experimental Therapeutics (ASPET) celebrated its centennial during the April 2008 Experimental Biology meeting held in San Diego, CA, USA. Objectives: This report summarizes a centennial symposium on past, present and future paradigms in drug discovery. The John Langley (1905) concept of ‘receptive substances’ initiated a cascade of cardinal discoveries for pharmacology. During the following 100 years, receptors achieved the status of well-defined multifunctional cellular proteins mediating all drug effects. The G-protein-coupled receptors (GPCRs) were discussed in relation to multiple targets they represent for clinically used or new medicines. The development of inbred and transgenic animal strains is a fundamental twentieth century achievement for biological research activities. Progress in treating CNS disorders still awaits breakthrough treatments. Drug development remains a risky and expensive venture; improvements are expected from emerging biomarker and translational medicine technologies. Future clinical research has to document the benefits that new medications provide to concerned stakeholders. Conclusions: We wish ASPET a new century of great achievements and acknowledge the dedication of several generations of colleagues, many of whom are our ‘unsung heroes’. They have left us a precious heritage to be pursued with passion in the quest for better medicines.

Concentration‐effect and dose‐response relations in clinical pharmacology

Concentration‐effect and dose‐response relations in clinical pharmacology

"Receptive substances": John Newport Langley (1852-1925) and his path to a receptor theory of drug action.

The concept of specific receptors that bind drugs or transmitter substances onto the cell, thereby either initiating biological effects or inhibiting cellular functions, is today a cornerstone of pharmacological research and pharmaceutical development. Yet, while the basic ideas of this concept were first explicitly formulated in 1905 by the Cambridge physiologist John Newport Langley (1852–1925), drug receptors remained hypothetical entities at least until the end of the 1960s. Without doubt, the development of receptor-subtype specific pharmaceuticals—especially the beta-adrenergic receptor antagonist propranolol (introduced in 1965)—promoted the acceptance of the receptor concept in pharmacology. It was only in the 1970s, however, that receptors began to be isolated as specific proteins of the cell membrane and that their composition and conformation began to be explored. During the last twenty years the modern techniques of molecular biology have helped to determine the genetic basis of receptor proteins, to identify their amino acid sequences, and to further elucidate their remarkable structural diversity as well as their similarities and evolutionary relationships. Numerous receptor types and subtypes have since been characterized.

The concept of transmitter receptors: 100 years on

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.

Catecholaminergic neurotransmission: flagship of all neurobiology

The paper describes, with focus on the first half of the century, the roles played by study of the sympathoadrenal system for developing modern neurobiology. Adrenaline isolated from extracts of adrenal medulla was the first intercellular messenger to be chemically identified and synthesized. Similarities between effects of adrenaline and sympathetic nerve stimulation led to the first concrete proposal of chemical neurotransmission. That effluent from a sympathetically or parasympathetically stimulated frog heart induced acceleration or slowing of an unstimulated recipient heart was the first conclusive proof of chemical neurotransmission. Acetylcholine (in parasympathetic or somatomotor) and noradrenaline (in sympathetic nerves) are the first identified mammalian neurotransmitters. The existence of a `receptive substance for adrenaline' represents the first proposal that target cells recognize and react to the released transmitter. Deviations from the `‐ergic' concept, in which sympathetic and parasympathetic nerves are termed `adrenergic' and `cholinergic', led to discovery of `non‐adrenergic, non‐cholinergic' nerves and a range of other transmitters. That some effects of e.g. sympathetic nerve stimulation are not blocked by any noradrenaline antagonist led to the recognition that some nerves utilize more than one transmitter. Noradrenaline in sympathetic nerves was the first neurotransmitter to be visualized in the light microscope. Catecholamines in adrenal medulla and sympathetic nerves were the first messengers to be shown to be stored in vesicles.

A modification of receptor theory. 1956.

A modification of receptor theory. 1956.

Melanocortin receptors: identification and characterization by melanotropic peptide agonists and antagonists.

Hormones are chemical messengers released from cells to act on and control the activity of other cells. Hormonal ligands initiate their actions by interacting with receptive substances (Langley, 1906) of the target cells. These receptors are proteins that are either integral components of the cell membrane or are localized cytoplasmically within cells. Ligand-receptor interaction results in either the stimulation or inhibition of cellular activity. Since most hormones bind rather specifically to receptors possessed by their target cells, labeling of hormonal ligands can be utilized to identify and localize cells within an animal. In this report we discuss what is presently known about melanocortin receptors (MCRs) as studied by the use of labeled melanotropic peptide ligands.

ChemInform Abstract: Cyclic Peptides. Part 23. Synthesis of Retro‐Enantio‐AM‐Toxin I.

AbstractTo characterize a receptive substance in an apple leaf of phytotoxic AM‐toxin I (I), the retro‐enantiomer (II) of the toxin is synthesized by cyclization of the α‐N deprotected derivative from the compound (III) via the intermediates (IVa) and (IVb).

Cyclic Peptides. XXIII. Synthesis of Retro-Enantio-AM-Toxin I

Abstract To characterize a receptive substance in an apple leaf of phytotoxic AM-toxin I, retro-enantiomer of the toxin was synthesized by the solution method. This analog showed no toxic activity, indicating that the specific backbone conformation of the toxin is essential for the activity.

Dale and the development of pharmacology. Lecture given at Sir Henry Dale Centennial Symposium, Cambridge, 17-19 September 1975.

The title of my lecture, ‘Dale and the development of pharmacology’, seems entirely appropriate in view of Dale's fundamental contributions to the subject; but it also contains a paradoxical element since Dale did not really consider himself a pharmacologist. He considered himself a physiologist, as he was by training and inclination. He trained in physiology with Langley and Gaskell in Cambridge, and after completing his medical course at Barts continued working as a physiologist with Starling as Sharpey Scholar. When at the age of 29 he became a pharmacologist by joining the Wellcome laboratories, he did not seem entirely happy at the transition, as is apparent from his writings in which he refers to the ergot ‘morass’ which he had entered, although he extracted some marvellous nuggets from it. Dale was atypical in his attitude of cautious reserve towards the drug receptor idea which has become so dominant a feature of pharmacology. He did not explain in terms of receptors the adrenaline reversal by ergot and although he knew of Langley's postulated ‘receptive substances’ he tended to emphasize our total ignorance of their nature. Interestingly though, in his 1919 Croonian Lecture he argued that the one receptive substance of which we knew something (because it could be studied apart from the cell) was the anaphylactic antibody, suggesting that its reaction with a specific antigen might provide an opportunity of studying drug-receptor interactions in a ‘test tube’. On a deeper level, Dale at times seemed almost surprised at the long range pharmacological-medical implications of his own discoveries. On one occasion, when discussing the early clinical uses of ganglion blocking drugs in hypertension he expressed astonishment that a symptomatic drug could be so effective in a chronic disease, probably reflecting the philosophy of Ehrlich who distinguished sharply between symptomatic and causal drugs. Yet, we know now from statistical evidence that treating the symptom hypertension, prolongs life. It can be said of Dale, as indeed of Ehrlich, that he was one of the great originators of pharmacology rather than a typical pharmacologist. Such people, by their very power and originality, cannot readily be accommodated within the framework of a restricted subject, though Dale's work is bound to exert a deep and lasting influence on the development and future of pharmacology.

Tissue binding of noradrenaline.

The substance noradrenaline is found in two sites in the body. First in certain nerves, and secondly in association with adrenaline in the adrenal medulla. In nerves this noradrenaline is stored in granules concentrated in the terminal nerve fibre. Its prime function is to transmit the effects of nerve impulses across the gap between the nerve ending and the cell served. This point is illustrated in figure 1 ( a ). When the nerve impulses, travelling down the nerve fibre, invades the nerve terminal, this releases some of the noradrenaline which passes into the space between nerve and muscle. This noradrenaline then diffuses across the gap to the smooth muscle, where it combines with a specialized part of the membrane, a part originally referred to by Langley (1905) as the ‘receptive substance’, and today more briefly termed the receptors. A consequence of this combination is a change in activity of the cell, the response. From this brief account it is clear that the most obvious binding sites for noradrenaline are the receptors for this substance on effector cells. Studies on the relationship between drug concentrations and the tissue response and the effect on this relationship of such irreversible blocking agents as phenoxybenzamine have led pharmacologists to suggest that only a small fraction, perhaps as low as 4 to 5% of the total receptors on the effector cell are involved in producing even a maximum response (Stephenson 1956). There is therefore a large reserve of ‘spare receptors’ (figure 1 ( a )), all potentially binding sites but not all simultaneously occupied under physiological conditions. A second binding site is shown in figure 1 ( b ). There are other substances and tissues in the body potentially capable of binding noradrenaline, the ground substance of con­nective tissue would be one example. Such binding would produce no response from the tissues themselves, and for this reason these sites are sometimes referred to as ‘silent receptors’ (Goldstein 1949). Nevertheless, the effector cell response may be affected in various ways. The response may be diminished by the silent receptors acting as a ‘site of loss’, so that less noradrenaline is available to the true receptors. There may be a secondary release from the silent receptors, so pro­longing the response. At present the evidence for the existence of these silent receptors is indirect and the extent of their involvement in vivo is obscure.

A modification of receptor theory.

A modification of receptor theory.

Sympathetic Blocking Agents

Until approximately a decade ago a sympathetic blocking agent was little more than a scientific curiosity but today the picture has been con­ siderably altered; certain sympathetic blocking chemicals have come into their own as valuable therapeutic agents. They have become available to us through the fine cooperation of our research scientists, a group which includes the chemist, the biologist, and the clinical investigator. In the development of these important drugs as available to physicians today is the pharmacologist who early recognized, with the inquisitive clinician, the important role that sympathetic predominance plays in the symptomatology of certain disorders which reflect imbalance of the autonomic nervous system. Some of these include neurogenic hypertension, certain peripheral vascular diseases, especially Raynaud's and probably Buerger's disease, herpes zoster, hyperthyroidism, tachycardia, glaucoma, exophthalmia, migraine headaches (spastic type), neurodermatoses, renal hypertension (in part neurogenic in origin?), vasospastic dysmenorrhea, causalgia, and probably some types of epilepsy. There is little doubt today that the autonomic nervous system plays a very important role, either directly or indirectly in many diseases, in terms of overactivity or underactivity of either portion of the autonomic nervous system, that is, of the parasympathetic or the sympathetic divisions. Our attention at the moment is directed toward suppressing, within desirable physiologic limits, the overactivity of the sympathetic portion of this system in certain undesirable conditions. This goal can be achieved by cer­ tain recently developed chemical compounds which have already established their value as therapeutic agents. Inspection of Fig. 1, a diagram by Hafkenschie1 & Sellers (1), which is an excellent modification of that previously employed (2), reveals various focal points of attack in the establishing of sympathetic or adrenergic blockade. The synonymous or interchanging use of the terms sympathetic and adrener­ gic blockade, a procedure which will be followed throughout this presentation should be noted. Adrenergic refers to that portion of the autonomic nervous system, namely the sympathetic portion, which responds to the action of adrenaline or adrenaline-like substances. These include epinephrine and norepinephrine in particular; any agent that blocks these substances which act in the region of the final arborization or distribution of sympathetic nerve fibers, that is, within the receptive substance of the end organs asso­ ciated with sympathetic innervation, is classified as a sympathetic or adrenergic blocking agent. On the other hand, one must bear in mind that

Effect of CO2 on Ameboid Changes in Motor Nerve Plates in Intercostal Muscle.

SummaryThe retracted motor nerve plates with wide, short projections were related to coarse, widely spaced cross striations, whereas expanded nerve plates with thin, elongated and moniliform processes were longer and separated by wider meshes than the retracted ones. 60% of the expanded motor nerve plates in the intercostal muscle accelerated in the transmission rate of the nervous impulses by carbon dioxide became twice the size of the relatively normal plates. Their processes were longer and separated by wider meshes than those of the normal controls. This morphologic expansion and extension of the processes of the plate by the proposed ameboid motion under the stimulus of the demand of increased functional activity evidently favors the transmission of the nerve impulse to the receptive muscle substance by increase of the surface area of the motor nerve plate. The differences in the histologic structure of motor nerve plates and muscle cross striations may be arranged in a graded series and are evidentl...

Relation of Muscle Receptive Substance to the Contractile Mechanism. Responses to Heat and Drugs

This paper reports further work in an investigation of muscle-receptive substance and contractile mechanism in smooth muscle fibers, already reported briefly. The results here reported seem to confirm the hypothesis that “This receptive substance is very labile to heat.” They seem to prove that the receptive substance can be destroyed without “killing” the contractile mechanism. The results, therefore, suggest that the receptive substance is not, as Langley postulated, a side chain of the contractile mechanism, but rather an independent structure or substance as postulated by Dixon. Method. The muscles here studied were the iris muscles of fetal pigs about 5 days before birth (length, 260 mm, plus or minus 10 mm). The fetuses were obtained from the recently killed mother, quickly excised, measured, and the marked heads placed in a mixture of hog saline and saline ice. For testing, the eyes of 7 fetuses of a litter were excised, placed in small individual pyrex glass cups in pairs, and covered with a glass plate. One eye of each pair was used as a control, the other for the test. The action of a drug or of a temperature change was measured by measuring the short diameter of the pupil before and after application. This measurement was made with fine bow dividers under illumination by both transmitted and reflected light, and the value read off on a diagonal scale. This value was corrected for any simultaneous change in the control. To determine the lability of the receptive substance to heat of 40°C, 6 of the 7 pairs of eyes were placed in a thermoregulated physiological saline bath at 40°C and a pair removed at regular intervals and cooled in a mixutre of saline and saline ice.

Autonomic Neuro-Effector Systems

SEVERAL reviews have been written recently dealing with the chemical transmission of nervous impulses. A monograph has now been published which gives, for the first time, an authoritative exposition of the views of the Harvard School. The authors have both written many papers describing investigations of the properties of adrenergic nerves. They have shown that stimulation of these nerves causes the liberation of at least two different substances. The clear presentation of the evidence for this conclusion forms the most valuable and impressive feature of the book. No one could question the experimental results, but their interpretation is still in doubt. The theory that drugs combine with a special receptive substance in the motor organ provides the only reasonable explanation of the specificity of drug action, but Cannon and Rosen-blueth's theory that this receptive substance is liberated with the drug into the blood stream seems unnecessarily complicated, and has met with opposition. Autonomic Neuro-Effector Systems By Prof. Walter B. Cannon Prof. Arturo Rosenblueth. (Experimental Biology Series.) Pp. xiv + 229. (New York: The Macmillan Co., 1937.) 17s. net.