Ammonia modifies enteric neuromuscular transmission through glial γ-aminobutyric acid signaling
Abstract
Impaired gut motility may contribute, at least in part, to the development of systemic hyperammonemia and systemic neurological disorders in inherited metabolic disorders, or in severe liver and renal disease. It is not known whether enteric neurotransmission regulates intestinal luminal and hence systemic ammonia levels by induced changes in motility. Here, we propose and test the hypothesis that ammonia acts through specific enteric circuits to influence gut motility. We tested our hypothesis by recording the effects of ammonia on neuromuscular transmission in tissue samples from mice, pigs, and humans and investigated specific mechanisms using novel mutant mice, selective drugs, cellular imaging, and enzyme-linked immunosorbent assays. Exogenous ammonia increased neurogenic contractions and decreased neurogenic relaxations in segments of mouse, pig, and human intestine. Enteric glial cells responded to ammonia with intracellular Ca2+responses. Inhibition of glutamine synthetase and the deletion of glial connexin-43 channels in hGFAP:: CreERT2+/−/connexin43f/fmice potentiated the effects of ammonia on neuromuscular transmission. The effects of ammonia on neuromuscular transmission were blocked by GABAAreceptor antagonists, and ammonia drove substantive GABA release as did the selective pharmacological activation of enteric glia in GFAP::hM3Dq transgenic mice. We propose a novel mechanism whereby local ammonia is operational through GABAergic glial signaling to influence enteric neuromuscular circuits that regulate intestinal motility. Therapeutic manipulation of these mechanisms may benefit a number of neurological, hepatic, and renal disorders manifesting hyperammonemia.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 01, 2017
- Source ID
- 10.1152/ajpgi.00154.2017
Entities
People
- Brian D Gulbransen
- David E. Fried
- Ralph E. Watson
- Simon C. Robson
Organizations
- Congressionally Directed Medical Research Programs
- Crohn's & Colitis Foundation of America
- Harvard Medical School
- Michigan State University
- National Institute of Diabetes and Digestive and Kidney Diseases