UCL Discovery

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.

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