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 PDGFRα(+) 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. Ca(2+) entry through voltage-dependent channels (Ca(V)3) enhances Ca(2+) release in ICC. Thus, we reasoned that hyperpolarization caused by purinergic responses in PDGFRα(+) cells, which are electrically coupled to ICC, might decrease inactivation of Ca(V)3 channels and activate Ca(2+) 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-PDGFRα(+) cell (SIP) syncytium generates a major motility behaviour. KEY POINTS: Propagating propulsive contractions initiated by the enteric nervous system are a major motility behaviour in the colon. A major component of contractions, necessary for propulsive contractions, occurs at cessation of enteric inhibitory neurotransmission (post-stimulus response) and is generated by interstitial cells of Cajal (ICC), which are electrically coupled to smooth muscle cells. The nature of enteric inhibitory neurotransmission shifts from proximal colon, where it is predominantly due to nitric oxide, to distal colon, where it is predominantly due to purine neurotransmitters. Different cells transduce nitric oxide and purines in the colon. ICC transduce nitric oxide, but another type of interstitial cell, PDGFRα(+) cells, transduces input from purinergic neurons. However, the post-stimulus responses in proximal and distal colon are still generated in ICC. This paper explores how integrated behaviours of ICC, PDGFRα(+) cells and smooth muscle cells accomplish propulsive motility in the colon.