Localisation and function of mechanosensory ion channels in colonic sensory neurons.

Abstract

Irritable Bowel Syndrome (IBS) is one of the most common functional disorders of the gastrointestinal tract. Visceral hypersensitivity is the most commonly reported symptom of IBS, yet is the least adequately treated. Mechanosensitive information from the colon is relayed to the CNS by extrinsic colonic primary afferent nerves which have their cell bodies within dorsal root ganglia (DRG). This thesis aims to identify the contribution of several putatively mechanosensitive ion channels (ASIC1, 2 and 3, TRPV4 and TRPA1) toward detection of mechanical stimuli in the colon. This involvement is assessed by both molecular and functional means. The abundance of each of these channels was assessed by comparing expression within whole DRG against that in specifically colonic DRG neurons using an in situ hybridization methodology developed as part of this PhD. The functional role TRPV4 and TRPA1 impart toward colonic mechanosensation was investigated by recording responses to mechanical stimuli from colonic primary afferent fibres and comparing the results from mice genetically modified to lack either TRPV4 or TRPA1 with those of their intact littermates. The results from these studies indicate expression patterns within whole DRG do not provide accurate representation of the organ of interest, with abundances of each of the channels investigated differing between colonic DRG cells and the whole DRG. In particular ASIC3 and TRPV4 are preferentially expressed in colonic DRG neurons, unlike ASIC2 and TRPA1. Further, TRPV4 is functionally restricted to detection of noxious mechanical stimuli in the colon, while expression of TRPA1 is more widespread and functionally less restricted. Each of these channels are each potential targets for the treatment of IBS as each affects specific aspects of colonic mechanotransduction.