Potassium channel regulation of murine gut motility and contractility

Understanding the mechanisms underlying gut motility and contractility is essential for elucidating gastrointestinal (GI) disorders and developing effective therapeutic interventions. Potassium (K+) channels are thought to play an important role in regulating GI function. This study investigates the role of KV7 and TREK channels in modulating gastrointestinal motility and smooth muscle contractility.

Methods: Gastrointestinal segments from C57BL/6OlaHsd mice were used. Electric field stimulation (EFS) was used to assess gastrointestinal smooth muscle contractility whilst an in-vitro colonic motility model was used to investigate the effects of KV7 and TREK channel activation upon gastrointestinal motor function. EFS evoked neurally mediated contractile responses mimicking the electrical impulses that lead to contractions and relaxations of gastrointestinal smooth muscle. The EFS parameters were 0.1ms pulse width, 10Hz (0.3Hz for the colon) frequency of 20 volts for 5 seconds at 5-minute intervals. Peak contractile responses were measured. The motility model generated consistent aborally propagating colonic
peristaltic motor complexes (CPMCs) reflecting both neuronal and myogenic functions of the tissue. CPMC frequency was measured using time in quiescence (TIQ) reflecting neuronal activity, while contractile activity was measured using CMPC amplitude reflecting colonic myogenic activity. Statistical analysis was by repeat measures one-way ANOVA on n≥4 experiments. P<0.05 was taken as significant.

Results: EFS responses induced rapid contractile responses in intestinal segments. In the colon, the Kv7 channel activator ML213, significantly decreased the EFS response from 0.94±0.11gto 0.60±0.06g at 1μM ML213(p<0.01) and from 1.01±0.11g to 0.42±0.10g at 3μM ML213(p<0.001). In the jejunum, the EFS response significantly decreased from 0.73±0.09g to 0.57±0.07g at 3μM ML213(p<0.01). The KV7 channel blocker XE991 increased baseline activity in the jejunum, with the area under the curve (AUC) significantly increasing from 441±48.3g·min to 498±52.1g·min (p<0.05) with 1μM XE991. Addition of the TREK 1 activator ML335 did not affect EFS responses in the ileum but significantly decreased responses in the colon from 0.68±0.11gto 0.37±0.06g at 30μM ML335(p<0.05). Motility studies revealed that ML213 inhibited colonic motility in a concentration-dependent manner, significantly increasing TIQ from 427±10.3s to 598±6.74s at 0.3μM ML213(p<0.001) and from 424±32.6s to 664±23.8s at 1μM ML213(p<0.05). CPMC amplitudes decreased with increasing ML213 concentration, but not significantly. XE991 significantly decreased TIQ from 369±35.8s to 240±11.3s at 1μM XE991(p<0.05) without affecting CPMC amplitude. In the presence of 0.1μM, 1μM and 3μM XE991 the effect of 0.3μM ML213 upon both TIQ and amplitude was blocked. ML335 also inhibited colonic motility in a concentration-dependent manner, significantly increasing TIQ from 487±17.5s to 608±14.5s at 1μM ML335(p<0.01), from 490±21.0s to 652±35.0s at 5μM ML335(p<0.01), and from 454±26.2s to 752±13.4s at 10μM ML335(p<0.01). However, ML335 did not affect CPMC amplitude, and it also decreased EFS responses, indicating TREK channels are on excitatory neurons.

Conclusions: The findings suggest that KV7 and TREK channels have a differential expression in the gut and regulate contractility and motility through neuronal activation. These data indicate these channels are primarily neuronal rather than myogenic, as the compounds had no significant effect on CPMC amplitudes. Targeting these channels could potentially treat motility disorders associated with irritable bowel syndrome.