Purinergic signalling: from discovery to current developments

NEW FINDINGS: What is the topic of this review? This is a personal historical review about the discovery and the main conceptual advances leading to our current understanding of purinergic signalling. The contributions of leading figures in the field are acknowledged. It includes the discovery of purinergic neuromuscular and synaptic transmission, cotransmission, the identification of P1 (adenosine), P2X nucleotide ion channel and P2Y nucleotide G protein-coupled receptors, the identity of ectonucleotidases and release of ATP from cells by mechanical stimulation and mechanosensory transduction. What advances does it highlight? It highlights the pathophysiology of purinergic signalling and recent therapeutic developments. This lecture is about the history of the purinergic signalling concept. It begins with reference to the paper by Paton & Vane published in 1963, which identified non-cholinergic relaxation in response to vagal nerve stimulation in several species, although they suggested that it might be due to sympathetic adrenergic nerves in the vagal nerve trunk. Using the sucrose gap technique for simultaneous mechanical and electrical recordings in smooth muscle (developed while in Feldberg’s department in the National Institute for Medical Research) of the guinea-pig taenia coli preparation (learned when working in Edith Bülbring’s smooth muscle laboratory in Oxford Pharmacology), we showed that the hyperpolarizations recorded in the presence of antagonists to the classical autonomic neurotransmitters, acetylcholine and noradrenaline, were inhibitory junction potentials in response to non-adrenergic, non-cholinergic neurotransmission, mediated by intrinsic enteric nerves controlled by vagal and sacral parasympathetic nerves. We then showed that ATP satisfied the criteria needed to identify a neurotransmitter released by these nerves. Subsequently, it was shown that ATP is a cotransmitter in all nerves in the peripheral and central nervous systems. The receptors for purines and pyrimidines were cloned and characterized in the early 1990s, and immunostaining showed that most non-neuronal cells as well as nerve cells expressed these receptors. The physiology and pathophysiology of purinergic signalling is discussed.