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TRPC Channels in Sensory Systems

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TRPC Channels in Sensory Systems TRPC Channels in Sensory Systems Kathryn Quick A thesis submitted for the degree of Doctor of Philosophy to University College London Wolfson Institute for Biomedical Sciences University College London 2011 Declaration I, Kathryn Quick, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. i Abstract Transient receptor potential canonical (TRPC) channels are a family of non-selective cation channels which have a wide range of physiological functions. In this thesis we used genetic approaches to investigate functional roles of TRPC3, TRPC6 We used the Cre/loxP system to delete TRPC3 exclusively from nociceptive neurons, using Nav1.8Cre, and from all dorsal root ganglion (DRG) neurons, using Advillin Cre. Inflammatory pain behavior was attenuated in both TRPC3 conditional null animals but acute mechanical, cold and thermal pain behavior was not affected. Microarray analysis identified a number of dysregulated pathways in the nociceptors of the TRPC3 conditional null mice, providing insights into inflammatory pain pathways. Given the similarity between TRPC channels we used a TRPC3/TRPC6 global double knockout to further investigate TRPC function. The TRPC3/TRPC6 double knockout mice were found to have attenuated mechanosensation specific to light touch, with no deficits in noxious mechanosensation, due to a reduction of rapidly adapting mechanically activated current in the small-medium DRG neurons. The TRPC3/TRPC6 double knockouts had no deficits in acute thermal or cold pain, or in neuropathic pain. The TRPC3/TRPC6 double knockouts were also behaviourally deaf, confirmed by auditory brainstem recordings. This work indicates a role for TRPC3 and TRPC6 in mechanosensation in sensory neurons and outer hair cells. ii Funding I thank the BBSRC and GlaxoSmithKline for funding this project. Publications Papers Raouf R, Quick K, Wood JN. (2010) Pain as a channelopathy. J Clin Invest 120(11):3745-52 iii 1 INTRODUCTION............................................................................................................1 1.1 PAIN AND NOCICEPTION ..............................................................................................1 1.2 NOCICEPTION AND DRG PRIMARY AFFERENT NEURONS .............................................2 1.2.1 Non- nociceptors.............................................................................................................................3 1.2.2 Nociceptors.....................................................................................................................................4 1.2.3 Silent nociceptors............................................................................................................................4 1.2.4 Gene expression in nociceptors ......................................................................................................5 1.2.5 Identification...................................................................................................................................6 1.2.6 Central projections .........................................................................................................................6 1.3 NOCICEPTION..............................................................................................................6 1.3.1 Mechanical .....................................................................................................................................6 1.3.2 Thermal...........................................................................................................................................8 1.3.3 Inflammatory pain ........................................................................................................................11 1.3.4 Neuropathic pain ..........................................................................................................................15 1.3.5 Central Processing .......................................................................................................................17 1.3.6 Voltage-gated sodium channels ....................................................................................................18 1.4 TRP CHANNELS ........................................................................................................20 1.4.1 Structure of TRP channels ............................................................................................................21 1.4.2 Transient Receptor Potential Canonical Channels.......................................................................22 1.4.3 Properties of TRPC channels........................................................................................................23 1.4.4 Modulation of TRPC channels......................................................................................................24 1.4.5 The TRPC3/6/7 subfamily.............................................................................................................25 1.4.6 Targeted gene deletion by homologous recombination in embryonic stem cells.......................... 31 1.4.7 Cre/loxP system ............................................................................................................................31 1.4.8 Flp/FRT system.............................................................................................................................32 1.5 AIMS .........................................................................................................................33 2 MATERIALS AND METHODS ..................................................................................34 2.1 MOLECULAR BIOLOGY .............................................................................................34 2.1.1 Gel electrophoresis.......................................................................................................................34 2.1.2 Polymerase Chain Reaction (PCR) ..............................................................................................34 2.1.3 Gel extraction ...............................................................................................................................35 2.1.4 DNA Digestions ............................................................................................................................35 2.1.5 Ligation of fragments into vectors ................................................................................................35 iv 2.1.6 Transformation .............................................................................................................................36 2.1.7 Preparation of DNA......................................................................................................................37 2.1.8 Sequencing.................................................................................................................................... 38 2.1.9 Southern Hybridization.................................................................................................................38 2.1.10 Genotyping............................................................................................................................... 39 2.1.11 RNA Extraction ........................................................................................................................41 2.1.12 cDNA synthesis ........................................................................................................................42 2.1.13 Reverse transcription Polymerase Chain Reaction..................................................................42 2.1.14 Quantitative PCR.....................................................................................................................42 2.2 BEHAVIOURAL PHENOTYPING ...................................................................................44 2.2.1 Rotarod .........................................................................................................................................44 2.2.2 Mechanical sensitivity...................................................................................................................44 2.2.3 Thermal sensitivity........................................................................................................................45 2.2.4 Cold plate .....................................................................................................................................46 2.2.5 Inflammatory pain models ............................................................................................................47 2.2.6 Neuropathic pain models..............................................................................................................49 2.2.7 Vestibular and hearing tests .........................................................................................................50 2.2.8 Preyer reflex test...........................................................................................................................50 2.2.9 Air righting ...................................................................................................................................50 2.2.10 Reaching response ...................................................................................................................51 2.2.11 Swim test ..................................................................................................................................51
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