The Nav1.9 channel regulates colonic motility in mice

Abstract

The colonic migrating motor complex (CMMC) is a major pattern of motility that is entirely generated and organized by the enteric nervous system. We have previously demonstrated that the Nav1.9 channel underlies a tetrodotoxin-resistant sodium current which modulates the excitability of enteric neurons. The aim of this study was to observe the effect of loss of the Nav1.9 channel in enteric neurons on mouse colonic motility in vitro. The mechanical activity of the circular muscle was simultaneously recorded from three sites, namely, proximal, mid- and distal, along the whole colon of male, age-matched wild-type and Nav1.9 null mice. Spontaneous CMMCs were observed in all preparations. The mean frequency of CMMCs was significantly higher in the Nav1.9 null mice (one every 2.87 ± 0.1 min compared to one every 3.96 ± 0.23 min in the wild type). The mean duration of CMMCs was shorter and the mean area-under-contraction was larger in the Nav1.9 null mice compared to the wild type. In addition, CMMCs propagated preferentially in an aboral direction in the Nav1.9 null mice. Our study demonstrates that CMMCs do occur in mice lacking the Nav1.9 channel, but their characteristics are significantly different from controls. Up to now, the Nav1.9 channel was mainly associated with nociceptive neurons and involved in their hyperexcitability after inflammation. Our result shows for the first time a role for the Nav1.9 channel in a complex colonic motor pattern.

Congenital insensitivity to pain: Fracturing without apparent skeletal pathobiology caused by an autosomal dominant, second mutation in SCN11A encoding voltage-gated sodium channel 1.9

“…Although the major consequence of the SCN11A mutation is diminished pain sensation, chronic diarrhea is common, and Na v 1.9 is expressed in myenteric neurons. (45,46) Na v 1.9 knockout mice have significantly increased intestinal motility, documenting that Na v 1.9 functions in colonic motor activity, (47) and perhaps explaining our patients' chronic diarrhea. Hyperhidrosis in the daughter too might represent autonomic dysfunction.…”

The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P

“…Therefore the phenotype is mainly caused by nerve dysfunction and not by its absence. The p.L811P variant causes a complex pattern of effects on neuronal subtype activity: it is excitatory in the enteric plexus (Na V 1.9 knockout mice have increased intestinal activity 5 ), in sweat glands leading to hyperhidrosis and in ano-rectal nociceptors showing these innervations are functioning; but it is inhibitory in most nociceptors and in infective inflammation (which also occur in sensory neuropathies where small unmyelinated nerves are absent). The Na V 1.9-CIP phenotype is unique and clearly clinically distinguishable from Na V 1.7-CIP, which is accompanied by anosmia but not gastrointestinal motility disturbances or muscle weakness.…”

“…2 In this light, epidermal thickening in GJB2 carriers 3,4 has been proposed as a possible advantage reducing infections and bacterial invasion through skin. 5,6 Moreover, in vitro functional studies demonstrated that the loss-of-functional GJB2 expression provides improved protection against gastrointestinal bacterial pathogens. 7 In particular, enteropathogenic Escherichia coli and Shigella flexneri may induce a strong selective effect, being the most common causes of diarrhoea.…”

A de novo gain-of-function mutation in SCN11A causes loss of pain perception

“…Prominent hyperhidrosis and gastrointestinal malfunction in the affected individuals may be a consequence of autonomic dysfunction. Na v 1.9 is indeed expressed in pacemaker neurons of the intestinal tract of rodents, and Scn11a knockout mice display altered colonic motility [35][36][37] .…”