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Mechanisms of Mechanotransduction by Dorsal Root Ganglia Neurons

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Mechanisms of Mechanotransduction by Dorsal Root Ganglia Neurons Mechanisms of Mechanotransduction by Dorsal Root Ganglia Neurons Liam J. Drew A thesis submitted for the degree of Doctor of Philosophy to University of London Department of Biology University College London 2004 1 UMI Number: U602667 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U602667 Published by ProQuest LLC 2014. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract The molecular mechanisms that mediate mammalian sensory mechanotransduction are poorly understood. Detection of mechanical events by sensory neurons of the dorsal root ganglia (DRG) is the primary event in the senses of touch, pressure-induced pain and proprioception. Recent work has demonstrated that the somatic membrane of cultured DRG neurons is a suitable system for studying physical transduction. In this thesis the responses of cultured DRG neurons to focal mechanical stimulation were investigated. It was shown that mechanical stimulation activated non-selective cation channels in these cells. The response properties of different subclasses of sensory neurons were characterised and were consistent with the presumedin vivo phenotypes of these cells. A number of antagonists of mechanically activated currents, with affinity in the low micromolar range, were identified; these included the pore blocking compounds gadolinium and ruthenium red and FM1-43 acted as a permeant blocker of mechano- sensitive channels. Modulation of mechanically activated currents by extracellular calcium was observed and it was shown that currents were regulated by the actin cytoskeleton and the extracellular matrix protein laminin. Investigation of null mutant mice revealed that the acid sensing ion channels 2 and 3, which are widely hypothesised to function in mammalian mechanosensation, did not contribute to mechanically activated currents. Venom of the marine snailConus ventricosus was found to block mechanically activated currents although the active component of this venom is yet to be identified. Overall, this work has shown that cultured DRG neurons are a useful system for studying mechanotransduction and has revealed a number of functional and pharmacological properties of the ion channels that underlie this process. 2 Declaration I, Liam Drew, did all the work presented in this thesis unless indicated otherwise. 3 Contents Title______________________________________________________________1 Abstract __________________________________________________________2 Declaration ________________________________________________________3 Contents __________________________________________________________4 List of Figures______________________________________________________ 9 List of Tables_______________________________________________________11 Acknowledgements _________________________________________________12 Abbreviations______________________________________________________14 Ion Channel Nomenclature____________________________________________16 1 Introduction ___________________________________________17 1.1 Dorsal root ganglia neurons: Structure and Function _________17 1 .1 . 1 General properties of DRG neurons__________________________ 19 1.1.1.1 Modality, fibre type and electrical properties of DRG neurons________________________________________________ 19 1.1.1.2 Differential ion channel expression by DRG neurons____________21 1.1.2 Mechanosensation by DRG neurons_________________________ 24 1.1.2.1 Mechanoreceptor types and end organs_______________________25 1.1.2.2 Mechanosensory Physiology_______________________________ 28 1.2 Sensory Mechanotransduction ____________________________33 1 .2 . 1 Mechanosensitive ion channels: General considerations_________ 33 1.2 . 2 Genetic screening of mechanosensory mutants in C. elegans and the DEG/ENaC superfamily of ion channels________ 36 1.2.2.1 Degenerin ion channels and othermec genes identified in C. elegans ______________________________________________38 1 .2.2.2 Epithelial sodium channels (ENaC)__________________________43 1.2.2.3 Acid sensing ion channels (ASIC)___________________________ 47 1 .2.2.4 Other DEG/ENaC channels implicated in mechanosensation_____ 60 1.2.3 Transient receptor potential (TRP) channels___________________61 4 1.2.3.1 TRP channels participate in invertebrate mechanosensation______ 63 1.2.3.2 Are there mechanically gated TRP channels expressed by mammals?_____________________________________________ 67 1.2.4 Chemically mediated mechanosensation_____________________ 70 1.2.5 Conclusion_____________________________________________ 72 13 Investigation of physical transduction mechanisms using cultured DRG neurons_____________________________ 74 1.3.1 Cultured DRG neurons as a system for studying ion channel function________________________________________ 74 1.3.2 Physical transduction by DRG neuronsin vitro ________________ 79 1.3.2.1 Heat transduction________________________________________ 79 1.3.2.2 Cold transduction,_______________________________________ 83 1.3.2.3 Thermal transduction conclusion____________________________8 6 1.3.2.4 Mechanotransduction_____________________________________ 8 8 1 .3.3 Studying mechanosensitive ion channels in heterologous systems______________________________ _________________ 93 1.4 Aims___________________________________________ 97 2 Materials and Methods_________________________________ 98 2 . 1 Cell Culture ____________________________________________ 98 2 .1 . 1 Culture of neonatal rat DRG neurons_________________________98 2 .1 . 2 Culture of adult mouse DRG neurons_________________________98 2.1.3 Preparation of superior cervical ganglia neurons_______________ 99 2.2 Electrophysiology_______________________________________ 99 2.2.1 Perforated-patch technique_________________________________ 100 2 .2 . 2 Cell selection and recording configuration____________________ 102 2.2.3 Standard Solutions_______________________________________ 103 2.2.4 Mechanical Stimulation and drug application__________________ 103 2.2.5 Data analysis____________________________________________ 105 5 3 Characterisation of mechanically activated currents in neonatal rat DRG neurons ___________________106 3.2 Introduction _______________________________________ 106 33 Materials and methods ___________________________ 107 3.4 Results ____________________________________________.108 3.4.2 Mechanical stimulation of the somata of DRG neurons evokes a cationic current__________________________________ 108 3.4.3 The substrate on which neurons are grown affects the kinetics ofMA currents___________________________________ 113 3.4.4 Subpopulations of DRG neurons are differentially mechanosensitive________________________________________ 115 3.4.5 MA currents are blocked by ruthenium red and gadolinium_____________________________________________ 1 2 2 3.4.6 MA currents are modulated by extracellular Ca2+ and Zn2+_______________________________________________ 125 3.4.7 Cytochalasin B inhibits MA currents_________________________13 2 3.4.8 FM1-43 is a permeant blocker of DRG mechanosensitive ion channels_____________________________ 134 3.4.9 Arachidonic acid inhibits MA currents_______________________ 136 3.4.10 MA currents evoked by different probe velocities_______________138 3.4.11 Relationship of MA currents to neurons’ chemosensitivity_______ 143 3.5 Discussion ______________________________________________146 3.5.2 DRG neuronal subtypes have distinct mechanosensitive phenotypesin vitro_______________________________________146 3.5.3 Mechanical stimulation evokes a cationic current_______________148 3.5.4 MA currents, the cytoskeleton and laminin____________________ 150 3.5.5 MA current pharmacology_________________________________ 155 3.5.6 Inhibition of MA currents by arachidonic acid_________________ 160 3.5.7 MA Currents at Different Probe Velocities: MA Current Kinetics_____________________________________ 161 6 4 Analysis of MA currents in adult mouse DRG neurons: Effect of ablating ASIC genes _________________165 4.1 Introduction ____________________________________________165 4.2 Materials and methods, __________________________________167 4.2.1 Generation of ASIC2 and ASIC3 null mutants_________________ 167 4.2.2 ASIC3 expression studies__________________________________168 4.2.3 Genotyping of ASIC1/2/3 mice_____________________________ 169 4.2.4 Electrophysiology, mechanical stimulation and drug application_________________________________________ 170 4.2.5 Immunocytochemistry____________________________________ 171 43 Results_________________________________________________172 4.3.1 Generation of ASIC3 null mutants___________________________ 172 4.3.2 Mechanically activated currents in large, wild-type DRG neurons___________________________________ 172 4.3.3 Mechanically activated currents were unchanged in large DRG neurons derived from ASIC2 and/or ASIC3 null mutants______________________________________ 176 4.3.4 Ruthenium red voltage-dependently blocks mechanically activated currents_____________________________181 4.3.5 Mechanically activated
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