Histamine causes influx via T-type voltage-gated calcium channels in an enterochromaffin tumor cell line: potential therapeutic target in adverse food reactions

Pfanzagl, Beatrix, Zevallos Herencia, Victor, Schuppan, Detlef, Pfragner, Roswitha and Jensen-Jarolim, Erika (2019) Histamine causes influx via T-type voltage-gated calcium channels in an enterochromaffin tumor cell line: potential therapeutic target in adverse food reactions. American Journal of Physiology-Gastrointestinal and Liver Physiology, 316 (2). G291-G303. ISSN 0193-1857

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Official URL: https://doi.org/10.1152/ajpgi.00261.2018

Abstract

The P-STS human ileal neuroendocrine tumor cells, as a model for gut enterochromaffin cells, are strongly and synergistically activated by histamine plus acetylcholine (ACh), presumably via histamine 4 receptors, and weakly activated by histamine alone. Sensing these signals, enterochromaffin cells could participate in intestinal intolerance or allergic reactions to food constituents associated with elevated histamine levels. In this study we aimed to analyze the underlying molecular mechanisms. Inhibition by mepyramine and mibefradil indicated that histamine alone caused a rise in intracellular calcium concentration ([Ca2+]i) via histamine 1 receptors involving T-type voltage-gated calcium channels (VGCCs). Sensitivity to histamine was enhanced by pretreatment with the inflammatory cytokine tumor necrosis factor-α (TNF-α). In accordance with the relief it offers some inflammatory bowel disease patients, otilonium bromide, a gut-impermeable inhibitor of T-type (and L-type) VGCCs and muscarinic ACh receptors, efficiently inhibited the [Ca2+]i responses induced by histamine plus ACh or by histamine alone in P-STS cells. It will take clinical studies to show whether otilonium bromide has promise for the treatment of adverse food reactions. The cells did not react to the nutrient constituents glutamate, capsaicin, cinnamaldehyde, or amylase-trypsin inhibitors and the transient receptor potential channel vanilloid 4 agonist GSK-1016790A. The bacterial product butyrate evoked a rise in [Ca2+]i only when added together with ACh. Lipopolysaccharide had no effect on [Ca2+]i despite the presence of Toll-like receptor 4 protein. Our results indicate that inflammatory conditions with elevated levels of TNF-α might enhance histamine-induced serotonin release from intestinal neuroendocrine cells.

Item Type: Article
Uncontrolled Keywords: Calcium/metabolism, Calcium Channel Blockers/pharmacology, Calcium Channels, L-Type/drug effects, Calcium Channels, T-Type/drug effects, Enterochromaffin Cells/drug effects, Histamine/metabolism, Humans, Membrane Potentials/drug effects
Subjects: B100 Anatomy, Physiology and Pathology
B400 Nutrition
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Elena Carlaw
Date Deposited: 28 May 2020 15:23
Last Modified: 28 May 2020 15:30
URI: http://nrl.northumbria.ac.uk/id/eprint/43269

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