Burnstock and the legacy of the inhibitory junction potential and P2Y1 receptors
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REVIEW ARTICLE
Burnstock and the legacy of the inhibitory junction potential and P2Y1 receptors Brian F. King 1 Received: 7 September 2020 / Accepted: 13 October 2020 # The Author(s) 2020
Abstract The synaptic event called the inhibitory junction potential (IJP) was arguably one of the more important discoveries made by Burnstock and arguably one of his finer legacies. The discovery of the IJP fundamentally changed how electromechanical coupling was visualised in gastrointestinal smooth muscle. Its discovery also set in motion the search for novel inhibitory neurotransmitters in the enteric nervous system, eventually leading to proposal that ATP or a related nucleotide was a major inhibitory transmitter. The subsequent development of purinergic signalling gave impetus to expanding the classification of surface receptors for extracellular ATP, not only in the GI tract but beyond, and then led to successive phases of medicinal chemistry as the P2 receptor field developed. Ultimately, the discovery of the IJP led to the successful cloning of the first P2Y receptor (chick P2Y1) and expansion of mammalian ATP receptors into two classes: metabotropic P2Y receptors (encompassing P2Y1, P2Y2, P2Y4, P2Y6, P2Y11–14 receptors) and ionotropic P2X receptors (encompassing homomeric P2X1–P2X7 receptors). Here, the causal relationship between the IJP and P2Y1 is explored, setting out the milestones reached and achievements made by Burnstock and his colleagues. Keywords IJP . P2Y receptor . Smooth muscle . Enteric nervous system
Abbreviations ENK GRP GPCR MRS2179 MRS2279
MRS2500
NOS PACAP PIT
SK channels Enkephalin Gastrin-releasing peptide G protein-coupled receptor 2′-Deoxy-N6-methyladenosine 3′,5′-bisphosphate 2-Chloro N6-methyl-(N)-methanocarba2′-deoxyadenosine-3′,5′-bisphosphate 2-iodo-N6-methyl-(N)methanocarba-2′-deoxyadenosine3′,5′-bisphosphate Nitric oxide synthase Pituitary adenylate-cyclase activating peptide 2,2-Pyridylisatogen Tosylate
* Brian F. King [email protected] 1
Research Department of Neuroscience, Pharmacology & Physiology (NPP), University College London (UCL), Gower Street, London WC1E 6BT, UK
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Small-conductance Ca2+-activated K+-channels Tetrodotoxin Vasoactive intestinal polypeptide
Introduction Geoffrey Burnstock (1929–2020) was widely acknowledged for his pioneering work on ATP receptors. He defined ATP receptors as P2 receptors, in deference to the already established class of adenosine receptors which he would call P1 receptors. Later, he and Charles Kennedy would broaden the P2 receptors to P2X and P2Y subtypes—an expanded classification based on the pharmacological profile for each subtype. Burnstock applied Paton’s criteria for the identification of a neurotransmitter, to define purinergic signalling as the release of packaged ATP from synaptic vesicles in enteric nerve endings. Afterwards, Burnstock proposed that ATP is stored and released with other transmitter substances by the same nerve endings in all peripheral nerves. The restlessness of his mind led to the proposal of familie
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