Furthering the debate on the role of interstitial cells of Cajal in enteric inhibitory neuromuscular neurotransmission

The gut, a muscular organ, performs a critical role in transporting ingested contents, yet it is also controlled to periodically stop transport to maximize digestion and toxin detection. The complex intraluminal composition and rheology challenge the mechanistic requirements of inhibitory neuromuscular neurotransmission. The interstitial cells of Cajal (ICCs)-generated slow wave may tune the promiscuous luminal chemical environment, which prepares the smooth muscle membrane potential for a depolarizing or hyperpolarizing response as needed. Slow waves are abolished during stimulation-induced inhibitory junction potentials (IJPs) due to purinergic-nitrergic tandem neurotransmission. Recent data demonstrating intact IJPs in a genomic knockout of ICCs provide rigorous evidence of the noncontribution of ICCs during evoked neurotransmission. This perspective article discusses the priority areas of investigations in enteric musculomotor transmission, for understanding its near-perfect design for chemical space sensing, as well as diseases in which the luminal transport braking process becomes dysfunctional, leading to delayed gastric emptying or intestinal transit.