Colitis decreases mechanosensitive K2P channel expression and function in mouse colon sensory neurons Abbreviated title: Mechanosensitive K2P channels in colon DRG neurons

TREK-1, TREK-2 and TRAAK are mechanosensitive two-pore domain K (K2P) channels thought to be involved in the attenuation of mechanotransduction. Because colon inflammation is associated with colon mechano-hypersensitivity, we hypothesized that the role of these channels in colon sensory (dorsal root ganglion, DRG) neurons would be reduced by colon inflammation. Accordingly, we studied the functional expression of mechanosensitive K2P channels in colon sensory neurons in both thoracolumbar (TL) and lumbosacral (LS) DRG that represent the splanchnic and pelvic nerve innervations of the colon, respectively. In colon DRG neurons identified by retrograde tracer previously injected into the colon wall, 62% of TL neurons and 83% of LS neurons expressed at least one of three K2P channel mRNAs; the proportion of LS neurons expressing the TREK-1 gene was greater than in their TL counterparts. In electrophysiological studies, single channel activities of TREK-1a, TREK-1b, TREK-2 and TRAAK-like channels were detected in cultured colon DRG neuronal membranes. After trinitrobenzene sulfonic acid-induced colon inflammation, we observed significant decreases in the amount of TREK-1 mRNA, in the response of TREK-2-like channels to membrane stretch, and in the whole cell outward current during osmotic stretch in LS colon DRG neurons. These findings document that the majority of DRG neurons innervating the mouse colon express mechanosensitive K2P channels and suggest that a decrease in their expression and activities contributes to the increased colon mechanosensitivity that develops in inflammatory bowel conditions.