Integrated responses of the SIP syncytium generate a major motility pattern in the colon

Abstract

The peristaltic reflex has been a central concept in gastrointestinal motility; however, evidence was published recently suggesting that post-stimulus responses that follow inhibitory neural responses provide the main propulsive force in colonic motility. This new concept was based on experiments on proximal colon where enteric inhibitory neural inputs are mainly nitrergic. However, the nature of inhibitory neural inputs changes from proximal to distal colon where purinergic inhibitory regulation dominates. In spite of the transition from nitrergic to purinergic regulation, post-stimulus responses and propulsive contractions were both blocked by antagonists of a conductance (ANO1) exclusive to interstitial cells of Cajal (ICC). How purinergic neurotransmission, transduced by PDGFR alpha(+) cells, can influence ANO1 in ICC is unknown. We compared neural responses in proximal and distal colon. Post-stimulus responses were blocked by inhibition of nitrergic neurotransmission in proximal colon, but P2Y1 receptor antagonists were more effective in distal colon. Ca2+ entry through voltage-dependent channels (Ca(V)3) enhances Ca2+ release in ICC. Thus, we reasoned that hyperpolarization caused by purinergic responses in PDGFR alpha(+) cells, which are electrically coupled to ICC, might decrease inactivation of Ca(V)3 channels and activate Ca2+ entry into ICC via anode-break upon cessation of inhibitory responses. Post-stimulus responses in distal colon were blocked by MRS2500 (P2Y1 receptor antagonist), apamin (SK channel antagonist) and NNC55-0396 (Ca(V)3 antagonist). These compounds also blocked propagating contractions in mid and distal colon. These data provide the first clear demonstration that integration of functions in the smooth muscle-ICC-PDGFR alpha(+) cell (SIP) syncytium generates a major motility behaviour.