Ca2+signaling driving pacemaker activity in submucosal interstitial cells of Cajal in the colon

Interstitial cells of Cajal (ICC) generate pacemaker activity responsible for phasic contractions in colonic segmentation and peristalsis. ICC along the submucosal border (ICC-SM) contributing to mixing and more complex patterns of colonic motility. We show the complex patterns of Ca 2+ signaling in ICC-SM and the relationship between ICC-SM Ca 2+ transients and activation of SMCs using optogenetic tools. ICC-SM displayed rhythmic firing of Ca 2+ transients ∼15 cpm and paced adjacent SMCs. The majority of spontaneous activity occurred in regular Ca2+ transients clusters (CTCs) that propagated through the network. CTCs were organized and dependent upon Ca 2+ entry through voltage-dependent Ca 2+ conductances, L- and T-type Ca 2+ channels. Removal of Ca 2+ from the external solution abolished CTCs. Ca 2+ release mechanisms reduced the duration and amplitude of Ca 2+ transients but did not block CTCs. These data reveal how colonic pacemaker ICC-SM exhibit complex Ca 2+ firing patterns and drive smooth muscle activity and overall colonic contractions. Synopsis How Ca 2+ signaling in colonic submucosal pacemaker cells couples to smooth muscle responses is unknown. This study shows how ICC modulate colonic motility via complex Ca 2+ signaling and defines Ca 2+ transients’ sources using optogenetic techniques.