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BQ788 Reveals Glial ETB Modulation of Neuronal Cholinergic and Nitrergic Pathways to Inhibit Intestinal Motility: ETB Signaling is Linked to POI.

British journal of pharmacology

Authors: E Mazzotta, I Grants, E Villalobos-Hernandez, S Chaudhuri, J L McClain, L Seguella, D M Kendig, B A Blakeney, K S Murthy, Reiner Schneider, Patrick Leven, Sven Wehner, A Harzman, J R Grider, B D Gulbransen, F L Christofi

BACKGROUND AND PURPOSE: ET-1 signaling modulates intestinal motility and inflammation, but the role of ET-1/ETB signaling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ETB signaling is a mechanism regulating neural-motor pathways of intestinal motility and inflammation.

EXPERIMENTAL APPROACH: We studied ETB signaling using: ETB 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 Sox10CreERT2; Rpl22-HAflx or ChATCre; Rpl22-HAflx mice, Sox10 ::GCaMP5g-tdT, Wnt1 ::GCaMP5g-tdT mice, muscle tension recordings, fluid-induced peristalsis, ET-1 expression, qPCR, western blots, 3-D LSM-immunofluorescence co-labeling studies in LMMP-CM and a POI model of intestinal inflammation (P<0.01 is significant).

KEY RESULTS: In the muscularis externa ETB is expressed exclusively in glia. ET-1 is expressed in RiboTag (ChAT)-neurons, isolated ganglia and intra-ganglionic varicose-nerve fibers co-labeled with peripherin or SP. Pharmacological analysis of neural evoked glial responses indicates that ET-1 release provides activity-dependent glial ETB modulation of Ca waves. BQ788 reveals amplification of glial and neuronal Ca responses and excitatory cholinergic contractions. The BQ788 effect is sensitive to L-NAME. Gliotoxins disrupt SaTX-induced glial-Ca waves and prevent BQ788 amplification of contractions. ETB is linked to inhibition of contractions and peristalsis. Inflammation causes glial ETB upregulation, SaTX-hypersensitivity and glial amplification of ETB signaling. In vivo BQ788 (i.p.,1mg/Kg) attenuates intestinal inflammation in POI.

CONCLUSION AND IMPLICATIONS: Enteric glial ET-1/ETB signaling provides dual modulation of neural-motor circuits to inhibit motility - It inhibits excitatory cholinergic neural-motor pathways and stimulates inhibitory nitrergic motor pathways. Amplification of glial ETB is linked to muscularis externa inflammation and possibly pathogenic mechanisms of postoperative ileus.

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PMID: 37198101

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