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.

The intrinsic primary afferent neurons (IPANs) of the guinea pig enteric nervous system express Na v 1.9 sodium channels that produce a persistent TTX-resistant current having a low activation threshold and slow gating kinetics. These neurons receive slow EPSPs induced mainly by the activation of neurokinin 3 receptors (NK3r). Here, we demonstrate that senktide, a specific NK3r agonist, potentiates the Na v 1.9 current (I Nav1.9 ) in IPANs. Using whole-cell patch-clamp recordings from IPANs in duodenum longitudinal muscle/myenteric plexus preparations, we show that short (1-5 s) and long (up to 1 min) applications of senktide, increase the I Nav1.9 peak current up to 13-fold. The effect, blocked by a NK3r antagonist SB235375 is transient, lasting ∼2 min and is due to a negative shift of the activation voltage by ∼20 mV and of fast inactivation by ∼10 mV. As a consequence, the window current resulting from the product of the activation and fast inactivation curves is shifted and enlarged. The transient effect of senktide is likely to be due to the fast desensitization of NK3r. Protein kinase C (PKC) activation with phorbol or oleoyl acetylglycerol also increases I Nav1.9 , although persistently, by inducing similar voltage-dependent changes. Current-clamp experiments showed that I Nav1.9 modulation by senktide lowers action potential threshold and increases excitability. The increase in I Nav1.9 by NK3r activation is also likely to amplify slow EPSPs generated in the IPANs. These changes in excitability potentially have a profound effect on the entire enteric synaptic circuit and ultimately on gut motility and secretion.

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