REVIEW The birth and postnatal development of purinergic signalling G. Burnstock, 1 B. B. Fredholm, 2 R. A. North 3 and A. Verkhratsky 3 1 Autonomic Neuroscience Centre, Royal Free and University College Medical School, London, UK 2 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden 3 Faculty of Life Sciences, University of Manchester, Manchester, UK Received 30 January 2010, accepted 15 February 2010 Correspondence: Professor G. Burnstock, Autonomic Neuroscience Centre, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK. E-mail: g.burnstock@ucl.ac.uk Abstract The purinergic signalling system is one of the most ancient and arguably the most widespread intercellular signalling system in living tissues. In this re- view we present a detailed account of the early developments and current status of purinergic signalling. We summarize the current knowledge on purinoceptors, their distribution and role in signal transduction in various tissues in physiological and pathophysiological conditions. Keywords adenosine, ATP, co-transmission, history, purinergic signalling, purinoceptors. The history of purines and pyrimidines began in 1776 when the Swedish Pharmacist Carl Wilhelm Scheele isolated uric acid from bladder stones (Scheele, V. Q. Examen Chemicum Calculi Urinari, Opuscula, 1776, 2, 73). Half a century later, in 1844, guanine was isolated by Unger from the faeces of guano sea birds (B. Unger, Ann. 1846, 58, 18). At the end of the 19th century, several principal purines (adenine and xanthine) and pyrimidines (thymine, cytosine and uracil) were discovered by Ludwig Karl Martin Leonhard Albrecht Kossel (1853– 1927; see Jones 1953, Bendich 1955). A particularly important role was played by the great Emil Fisher, who started a study of the structure of caffeine and related compounds (Fischer 1881). He solved the structures and confirmed them by synthesis. His elucidation of the structures of the group of compounds he denoted ‘purines’ (Fischer 1907) was an important reason for his Nobel prize in 1902. The term ‘pyrimidines’ was introduced by Pinner (1885). An arduous task of deter- mining the sugar part of nucleosides (and nucleotides) followed and was finally solved by Phoebus Aaron Levene (Levene & Jacobs 1908, Levene & Tipson 1931). In 1927, Gustav Embden and Margarete Zimmer- mann described adenosine monophosphate in skeletal muscle (Embden & Zimmermann 1927). Adenosine 5¢- triphosphate (ATP) was discovered in 1929 indepen- dently by Karl Lohmann in Germany and by Cyrus Hartwell Fiske and Yellagaprada SubbaRow in the USA (Fiske & SubbaRow 1929, Lohmann 1929). Lohmann’s publication appeared several months earlier than the paper by Fiske and SubbaRow, and yet the latter had obtained the first evidence for ATP probably as early as in 1926 (Fig. 1). Whether Fiske briefed Otto Meyerhof, who was Lohmann’s director, about his discovery or not remains a matter of doubt (the dramatic history of ATP discovery is described in detail in Maruyama 1991). In the following decade the role of ATP in cell energetics was firmly established and the concept of the ‘high-energy phosphate bond’ was introduced by Fritz Lipman (Lipman 1941). Early studies of the extracellular effects of purines Adenine was detected in blood in 1914 (most probably in the form of the adenosine 5¢-monophosphate, AMP; Bass 1914), and later it was suggested that it had inhibitory properties (Freund 1920). At about the same time, Thannhauser & Bommes (1914) claimed that, unlike adenosine, adenine injected subcutaneously in humans was not toxic. In 1926, IG Farben in Germany started to isolate potential cardio-stimulant substances from the heart and developed an extract that contained mostly AMP. Extracellular signalling roles for purines were exper- imentally discovered by Drury & Szent-Gyo ¨ rgyi (1929) Acta Physiol 2010, 199, 93–147 Ó 2010 The Authors Journal compilation Ó 2010 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2010.02114.x 93