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

Abstract

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.

Colligative Property of ATP: Implications for Enteric Purinergic Neuromuscular Neurotransmission

“…However, the prolonged release of nitric oxide prevents the restoration of membrane potential to baseline and aims to maintain the hyperpolarization. This is manifested as the slow inhibitory junction potential (sIJP), unambiguously recorded by several investigators across decades (Figure 1; Bennett et al, 1966; Atanasova et al, 1972; Smith et al, 1990; Hirst et al, 2004; Allego et al, 2008; Chaudhury et al, 2011, 2012; Chaudhury, 2016a). Following the paradigm-shifting demonstration of ATP as a neurotransmitter using gut tissues (Burnstock et al, 1970), there was a gap of several decades in which the VNUT could not be identified within the synaptic vesicles.…”

“…Evoked enteric inhibitory neuromuscular neurotransmission involves the sequential release of purines (most importantly, ATP) and the gas nitric oxide (NO), synthesized by neuronal nitric oxide synthase (nNOS) at the membranes of nerve terminals (Chaudhury et al, 2011, 2012; Chaudhury, 2014, 2015a, 2016a,b). While ATP is stored in the vesicles of the nerve terminals, NO is synthesized de novo (Chaudhury, 2016a). The released ATP during evoked neurotransmission hyperpolarizes the smooth muscle membrane (Chaudhury, 2016a).…”

“…While ATP is stored in the vesicles of the nerve terminals, NO is synthesized de novo (Chaudhury, 2016a). The released ATP during evoked neurotransmission hyperpolarizes the smooth muscle membrane (Chaudhury, 2016a). In a span of a few 100 ms, the membrane potential endeavors to swing back to its resting stage.…”

“…The enteric inhibitory neurotransmission is represented electrophysiologically by the fast and slow IJP, mediated by the purine nucleotide ATP and NO, respectively (Chaudhury et al, 2011, 2012; Chaudhury, 2016a). While ATP is released from vesicles (Chaudhury et al, 2012), NO is synthesized by nNOS at the nerve terminal membrane (Chaudhury et al, 2009, 2011; Chaudhury, 2014).…”

“…The significance of this important observation is unknown. The dynamics of release of ATP/NO and Ach is also not known (Chaudhury, 2016a). A common observation is the occurrence of a contractile response at the end of an episode of relaxation during post-stimulus mechanical recordings of gastrointestinal muscle strips (Figure 1; Anuras et al, 1974).…”