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This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Roles of TRPM8 and TRPM3 in sensory transduction Quallo, Talisia Esme Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 25. Sep. 2021 Roles of TRPM8 and TRPM3 in sensory transduction Thesis submitted for the degree of Doctor of Philosophy King’s College London Talisia Esme Quallo Wolfson Centre for Age-Related Diseases School of Biomedical Health Sciences King’s College London 2010-2014 1 Abstract Primary afferent neurons are equipped with sensory transduction channels which allow the conversion of physical and chemical stimuli into electrical signals. TRP channels are a heterogeneous superfamily of largely non-selective cation channels, which have been implicated in a myriad of sensory transduction mechanisms from the detection of temperature to the sensation of touch. Many TRP channels are key targets for the study of pain physiology due to their polymodal activation and expression in small diameter, unmyelinated sensory fibres. The aim of my project was to examine the roles of TRP channels in sensory transduction mechanisms. Three results chapters focusing on three different TRP channels are presented. A novel role for the established cold thermosensor, TRPM8, as a cellular osmosensor was determined. The studies presented establish that TRPM8 is activated by increases in extracellular osmolality and is partially activated at normal physiological osmolalities. Cool temperatures increase the sensitivity of TRPM8 to osmotic stimuli and activation of phospholipase enzymes modulates activation of TRPM8 by hyperosmotic solutions. TRPM8 is expressed within sensory neurons where it functions as the chief detector of increased osmolality in addition to a molecular sensor of cold sensations. The role of TRPM3 as a candidate heat transduction channel is examined. The findings presented demonstrate that recombinantly expressed TRPM3 channels are heat-sensitive and mice lacking functional TRPM3 channels lose a population of heat-activated neurons and have impaired behavioural responses to noxious heat. Moreover, modulation of TRPM3 by intracellular pathways downstream of G-protein coupled receptor activation has been determined. Activation of TRPM3 in sensory neurons is shown to be robustly inhibited by morphine in a predominantly mu-opioid receptor and Gi dependent mechanism. Additionally the role of TRPM3 in several pain states is examined. Finally, this thesis reports on the characterisation of a medium-throughput CGRP release assay for examining activation of TRPA1 natively expressed on the central terminals of dorsal root ganglion neurons. Activation of TRPA1 expressed on spinal cord synaptosomes by a selection of agonists evokes a concentration-dependent release of CGRP which is inhibited by TRPA1 antagonists. The VGCC subtypes important for TRPA1 and depolarisation-induced CGRP release are examined. 2 Acknowledgements I would like to thank Stuart, my primary supervisor for offering me this PhD studentship four years ago and for being such a consistently supportive and encouraging supervisor. I have enjoyed being part of the Bevan lab so much and feel very lucky to have been a member of such a great research team. I would also like to thank David for being an incredible mentor and for always being there to answer my many, many questions. It has been so reassuring to have such expert guidance on tap at all times! I would also like to thank Clive, firstly for his help with behavioural techniques and dissections and secondly for being great company and a fountain of knowledge! I would also like to thank Adrian and Lisa for their help and guidance during my time spent at Lilly. I would like to thank my good friend and fellow lab member, Nisha, for her ability to instil calm and for all of her help both inside and outside of the lab. Thank you for brightening up long lab days and for your unrelenting kindness. I am not sure whether I could have done it without all of your pep talks! I would like to thank Liz, Jack, Julie, Chancie, Emma, Byron and Dave for welcoming me into the Wolfson CARD and for all of those much needed dancing sessions! I would also like to thank Clare and Ed for the essential office tea and biscuit breaks, and discussions on important matters, like the bizarre television programmes of our childhoods. Clare, I can’t believe our four years together has flown by so quickly. Best of luck in your new job, I can’t wait to hear all about it! I would like to thank all of my friends for keeping me sane over the last four years; I couldn’t have done it without you all. I would like to thank my Mum, Dad and sister, Marsha, for their unwavering encouragement and love. I certainly wouldn’t be where I am now without it. Lastly, I would like to thank Neil, for being my best friend and for putting up with me for so long. 3 Table of Contents ABSTRACT ........................................................................................................................................ 2 ACKNOWLEDGEMENTS .................................................................................................................... 3 TABLE OF CONTENTS ........................................................................................................................ 4 TABLE OF FIGURES ........................................................................................................................... 9 TABLE OF TABLES ........................................................................................................................... 11 ABBREVIATIONS AND ACRONYMS ................................................................................................. 12 CHAPTER 1. GENERAL INTRODUCTION ..................................................................................... 15 1.1 INTRODUCTION TO SENSATION.................................................................................................... 16 1.2 THE SOMATOSENSORY NERVOUS SYSTEM ...................................................................................... 16 1.3 THE PRIMARY AFFERENT NEURON ................................................................................................ 16 1.3.1 Sensory nerve modalities ................................................................................................ 17 1.3.2 Primary afferent nerve fibre types.................................................................................. 17 1.3.3 Nociceptive nerve fibres ................................................................................................. 19 1.3.4 Central projections of primary afferent neurons ............................................................ 20 1.4 TRP CHANNELS ....................................................................................................................... 21 1.4.1 Discovery ........................................................................................................................ 22 1.4.2 Sub-families .................................................................................................................... 22 1.4.3 Structure ......................................................................................................................... 22 1.4.4 Mammalian TRP channels .............................................................................................. 23 1.5 THE MOLECULAR BASIS OF SENSATION .......................................................................................... 27 1.5.1 Thermosensation ............................................................................................................ 28 1.5.2 Mechanosensation ......................................................................................................... 35 1.5.3 Osmosensation ............................................................................................................... 38 1.1.1 Chemosensation ............................................................................................................. 39 1.6 PAIN AND INFLAMMATORY SENSITISATION .................................................................................... 41 CHAPTER 2. GENERAL MATERIAL AND METHODS ..................................................................... 43 2.1 CELL CULTURE
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