| First Author | Mazzotta E | Year | 2023 |
| Journal | Br J Pharmacol | Volume | 180 |
| Issue | 19 | Pages | 2550-2576 |
| PubMed ID | 37198101 | Mgi Jnum | J:349321 |
| Mgi Id | MGI:7642031 | Doi | 10.1111/bph.16145 |
| Citation | Mazzotta E, et al. (2023) BQ788 reveals glial ET(B) receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus. Br J Pharmacol 180(19):2550-2576 |
| abstractText | 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. |
