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

Abstract

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, …