Agonist-Evoked Ca2+ Signaling in Enteric Glia Drives Neural Programs That Regulate Intestinal Motility in Mice
| Autor: | Brian D. Gulbransen, David Fried, Jonathon L. McClain |
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| Rok vydání: | 2015 |
| Předmět: |
WT
wild type Agonist medicine.drug_class Motility CMMC colonic migrating motor complex Enteric Nervous System Calcium in biology DREADD designer receptors exclusively activated by designer drugs PGF2α prostaglandin F2α Muscle tension medicine Gut lcsh:RC799-869 Receptor GPCR G protein-coupled receptor Migrating motor complex Original Research ENS enteric nervous system Hepatology Glial fibrillary acidic protein biology GFAP glial fibrillary acidic protein Gastroenterology CNO clozapine-N-oxide ADP adenosine diphosphate Intestine Cell biology Chemogenetic Autonomic Biochemistry nervous system LMMP longitudinal muscle myenteric plexus biology.protein DMEM Dulbecco’s modified Eagle medium lcsh:Diseases of the digestive system. Gastroenterology Enteric nervous system BCH bethanechol tTA tetracycline-controlled transactivator protein EFS electrical field stimulation HA hemagglutinin |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 1, Iss 6, Pp 631-645 (2015) Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2015.08.004 |
| Popis: | Background & Aims: Gastrointestinal motility is regulated by enteric neural circuitry that includes enteric neurons and glia. Enteric glia monitor synaptic activity and exhibit responses to neurotransmitters that are encoded by intracellular calcium (Ca2+) signaling. What role evoked glial responses play in the neural regulation of gut motility is unknown. We tested how evoking Ca2+ signaling in enteric glia affects the neural control of intestinal motility. Methods: We used a novel chemogenetic mouse model that expresses the designer receptor hM3Dq under the transcriptional control of the glial fibrillary acidic protein (GFAP) promoter (GFAP::hM3Dq mice) to selectively trigger glial Ca2+ signaling. We used in situ Ca2+ imaging and immunohistochemistry to validate this model, and we assessed gut motility by measuring pellet output and composition, colonic bead expulsion time, small intestinal transit time, total gut transit time, colonic migrating motor complex (CMMC) recordings, and muscle tension recordings. Results: Expression of the hM3Dq receptor is confined to GFAP-positive enteric glia in the intestines of GFAP::hM3Dq mice. In these mice, application of the hM3Dq agonist clozapine-N-oxide (CNO) selectively triggers intracellular Ca2+ responses in enteric glia. Glial activation drove neurogenic contractions in the ileum and colon but had no effect on neurogenic relaxations. CNO enhanced the amplitude and frequency of CMMCs in ex vivo preparations of the colon, and CNO increased colonic motility in vivo. CNO had no effect on the composition of fecal matter, small intestinal transit, or whole gut transit. Conclusions: Glial excitability encoded by intracellular Ca2+ signaling functions to modulate excitatory enteric circuits. Selectively triggering glial Ca2+ signaling might be a novel strategy to improve gut function in motility disorders. Keywords: Autonomic, Chemogenetic, Enteric Nervous System, Intestine, Gut |
| Databáze: | OpenAIRE |
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