Secretin targets interstitial cells of Cajal to regulate intestinal motility

Secretin plays an important role in gastrointestinal (GI) physiology by
stimulating bicarbonate and bile secretion to neutralize acidic chyme and
aid in lipid absorption. Secretin also slows intestinal motility, an
effect attributed to vagal afferent pathways. In this study, we show
evidence for a novel function of secretin involving a non-neural mechanism
mediated by interstitial cells of Cajal (ICC). Secretin receptors (SCTR)
were found to be abundantly expressed by ICC in the deep muscular plexus
(ICC-DMP) of the small intestine. Secretin reduced small intestinal
contractions in the presence of tetrodotoxin (TTX) and suppressed
cholinergic transmission. Ca2+ imaging demonstrated that the inhibitory
effects of secretin occur through inhibition of Ca2+ transients in
ICC-DMP, an effect previously linked to inhibition of intestinal
contractions. SCTRs are linked to function via Gas, secretin increased
cAMP levels in ICC-DMP, and responses were inhibited by a selective PKA
antagonist. Our data suggest that PKA activation is in some way linked to
inhibition of IP3 receptors, as the robust increase in Ca2+ transients in
ICC-DMP due to uncaging of IP3 was blocked by secretin. Conclusions from
these experiments outline a new concept for ICC-DMP: these cells serve as
a focus point in which signaling from the enteric nervous system and
hormones converge and integrate mechanisms regulating intestinal motility.
In the case of secretin, this may result in slowing of intestinal transit
to enhance digestion and absorption of nutrients.