SAMHITA CHAUDHURI

Background and Purpose ET‐1 signalling modulates intestinal motility and inflammation, but the role of ET‐1/ET B receptor signalling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ET B signalling regulates neural‐motor pathways of intestinal motility and inflammation. Experimental Approach We studied ET B signalling using: ET B drugs (ET‐1, SaTX, BQ788), activity‐dependent stimulation of neurons (high K + ‐depolarization, EFS), gliotoxins, Tg (Ednrb‐EGFP)EP59Gsat/Mmucd mice, cell‐specific mRNA in Sox10 CreERT2 ;Rpl22‐HAflx or ChAT Cre ;Rpl22‐HAflx mice, Sox10 CreERT2 ::GCaMP5g‐tdT, Wnt1 Cre2 ::GCaMP5g‐tdT mice, muscle tension recordings, fluid‐induced peristalsis, ET‐1 expression, qPCR, western blots, 3‐D LSM‐immunofluorescence co‐labelling studies in LMMP‐CM and a postoperative ileus (POI) model of intestinal inflammation. Key Results In the muscularis externa ET B receptor is expressed exclusively in glia. ET‐1 is expressed in RiboTag (ChAT)‐neurons, isolated ganglia and intra‐ganglionic varicose‐nerve fibres co‐labelled with peripherin or SP. ET‐1 release provides activity‐dependent glial ET B receptor modulation of Ca 2+ waves in neural evoked glial responses. BQ788 reveals amplification of glial and neuronal Ca 2+ responses and excitatory cholinergic contractions, sensitive to L‐NAME. Gliotoxins disrupt SaTX‐induced glial‐Ca 2+ waves and prevent BQ788 amplification of contractions. The ET B receptor is linked to inhibition of contractions and peristalsis. Inflammation causes glial ET B up‐regulation, SaTX‐hypersensitivity and glial amplification of ET B signalling. In vivo BQ788 (i.p., 1 mg·kg −1 ) attenuates intestinal inflammation in POI. Conclusion and Implications Enteric glial ET‐1/ET B signalling provides dual modulation of neural‐motor circuits to inhibit motility. It inhibits excitatory cholinergic and stimulates inhibitory nitrergic motor pathways. Amplification of glial ET B receptors is linked to muscularis externa inflammation and possibly pathogenic mechanisms of POI.