Cell signalling by extracellular nucleotides and derivatives
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Dr Brian King graduated in Physiology (1976) and Pharmacology (1980) at the University of Glasgow, Scotland where he trained in neuroscience. His first academic appointment was at the Mayo Clinic in Rochester, Minnesota (1980-85) where he worked in the Department of Physiology and studied the biophysical and signalling properties of sympathetic neurons innervating the gastrointestinal tract. After 5 years in the US, Dr. King moved first to McGill University (Montreal, Canada; 1985), then to the London Hospital Medical School (London England, 1986-1989) to study the sensory systems of the gastrointestinal tract. He took time out of academia to join SmithKline Beecham (1989-1992) and study a neurological disorder called the Irritable Bowel Syndrome. Returning to UCL (1992), he was involved immediately in the isolation and characterisation of the first of the recombinant nucleotide receptors, P2Y1. Dr. King has spent the last 13 years at UCL studying the purinoceptor family of signalling molecules which now encompasses over 25 receptor subtypes. Dr. King sits on advisory boards for nucleotide signalling (IUPHAR P2X and P2Y Nomenclature Subcommittees) and regularly contributes to the Handbook of Receptor Classification (Sigma RBI) and Guide to Receptors and Channels (Br J Pharmacol).
Nucleotides are naturally-occurring compounds found in all living cells, where they have well-defined biochemical and physiological roles. Inside the cell, nucleotides represent the major "energy currency" for biochemical metabolism. When released into the extracellular space, nucleotides also represent a novel way for cells to talk to their neighbours. Nucleotides and their derivatives can activate a large number of membrane-bound signalling proteins, collectively called the purinoceptor family [see Figure 1]. All cells possess purinoceptors - often more than one subtype - and, as a result, these signalling proteins affect every aspect of human physiology. My staff and students work mainly on the signalling properties of the mammalian purinoceptor family, which are studied by cloning individual members into a host cell (e.g. Xenopus oocytes, 1321N1 human astrocytoma cells). We often clone two or more purinoceptors to make heteromeric assemblies of signalling molecules. Occasionally, we also co-express purinoceptors with other types of signalling proteins to investigate receptor-receptor crosstalk. Already, we have studied how purinoceptors can affect TRP and ENaC channels and now are focussing on their actions on AQP (water) channels. The results of our cloning experiments are compared with results from parallel studies of tissues and organs containing key members of the purinoceptor family. I work closely with other scientists in the Department - and throughout UCL - to model signalling systems which employ purinoceptors, and investigate unresolved issues in human physiology. Some of our studies include the role of extracellular nucleotides in i) bone modelling and osteoporosis, ii) control of breathing, iii) tubule function in kidney, iv) blood platelet function in control of bleeding, v) astrocyte growth following brain injury, vi) signalling in sensory nerve pathways, including the ear, vi) control of the urinary bladder and vii) control of gastrointestinal motility. Recently, I have been working with an international collaborative group on the actions of alcohol on the reward/addiction centre of the brain.
Figure 1 The purinoceptor family showing members of the five subtypes. Each subtype is activated by 4 prototypic classes of molecules that possess the purine moiety, but with various extensions to this chemical template. Adenine is the simplest form and the dinucleotide (Ap3A) is the most complex. P2X receptors are ATP gated ion-channels, whereas the remainder are G protein- coupled receptors
- Nicke A and King BF (2006) Heteromerization of P2X receptors In: Biological and Biophysical Aspects of Ligand-Gated Ion Channel Receptor Superfamilies Ed: HR Arias, Research SignPost.
- Bailey MA, Shirley DG, King BF, Burnstock G and Unwin RJ (2006) Extracellular nucleotides and renal function In: The Kidney Ed: RJ Alpern and SC Hebert, Elsevier Publications, Edition 4
- King BF (2006) P2 receptors In: The Sigma-RBI Handbook of Receptor Classification and Signal Transduction Ed: KJ Watling, Edition 5
- King BF and Townsend-Nicholson A (2003) Nucleotide and Nucleoside Receptors Tocris Reviews, 23, 1-12
- King BF (2002) Purinergic receptors. In: Structure and Function of GPCRs in the Nervous System, Ed: M. Pangalos and C. Davies, Oxford University Press.
- King BF (1998) Molecular biology of P2X purinoceptors Ed: G. Burnstock, J.G. Dobson, B.T. Liang & J. Linden, Kluwer Academic Publications
- Davies DL, Asatryan L, Kuo SF, Woodward JJ, King BF, Alkana RL, Xiao C, Sun H, Hu XQ, Hayrapetyan V, Lovinger DM and Machu TK (2006) The effects of ethanol on ATP-gated purinergic and 5-HT3 receptors Alcoholism: Clin. Exp. Res., 30, 349-358.
- King BF and Townsend-Nicholson A (2006) Prejunctional P2X receptors and postjunctional P2Y receptors activated by alpha,beta-methyleneATP and relaxing guinea-pig taenia coli Br. J. Pharmacol., in press
- King BF, Liu M, Townsend-Nicholson A, Pfister J, Padilla F, Ford AP & Gever J, Oglesby I, Schorge S and Burnstock G (2005) Antagonism of ATP responses at P2X receptor subtypes by the pH indicator dye, Phenol red Br. J. Pharmacol., 145, 313-322
- Wildman SS, Marks J, Churchill LJ, Peppiatt CM, Chraibi A, Shirley DG, Horisberger J-D, King BF and Unwin RJ (2005) Regulatory interdependence of cloned epithelial Na+ channels and P2X receptors J. Am. Soc. Nephrol., 16, 2586-2597
- Davies DL, Kochegarov AA, Kuo S, Kulkarni AA, Woodward JJ, King BF and Arkana RL (2005) Ethanol differentially affects P2X3 and P2X4 receptor subtypes expressed in Xenopus oocytes Neuropharmacology, 49, 243-253
- King BF, Knowles ID, Burnstock G and Ramage AG (2004) Investigation of the effects of P2 purinoceptor ligands on the micturition reflex in female urethane anaesthetized rats Br. J. Pharmacol., 142, 519-530
- Wildman SS, Hooper KM, Turner CM, Sham J, Lakatta EG, King BF, Unwin RJ and Sutters M (2003) The isolated cytoplasmic C-terminus of polycystin-1 prolongs ATP-stimulated chloride conductance through increased Ca2+ entry Am. J. Physiol., 285, F1168-F1178
- Wildman SS, Unwin RJ and King BF (2003) Extended pharmacological profile of rat P2Y2 and rat P2Y4 receptors and their sensitivity to extracellular H+ and Zn2+ ions Br. J. Pharmacol., 140, 1177-1186