Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5

Abstract Bile acids are recognised as bioactive signalling molecules. While they are known to influence arrhythmia susceptibility in cholestasis, there is limited knowledge about the underlying mechanisms. To delineate mechanisms underlying fetal heart rhythm disturbances in cholestatic pregnancy, w...

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Autores principales:	Effendi Ibrahim, Ivan Diakonov, Dulasi Arunthavarajah, Teresa Swift, Mary Goodwin, Saraid McIlvride, Vanya Nikolova, Catherine Williamson, Julia Gorelik
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b9f80aa5866a41af9eb558fcc06bf458
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spelling	oai:doaj.org-article:b9f80aa5866a41af9eb558fcc06bf4582021-12-02T12:32:35ZBile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR510.1038/s41598-018-25569-42045-2322https://doaj.org/article/b9f80aa5866a41af9eb558fcc06bf4582018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25569-4https://doaj.org/toc/2045-2322Abstract Bile acids are recognised as bioactive signalling molecules. While they are known to influence arrhythmia susceptibility in cholestasis, there is limited knowledge about the underlying mechanisms. To delineate mechanisms underlying fetal heart rhythm disturbances in cholestatic pregnancy, we used FRET microscopy to monitor cAMP release and contraction measurements in isolated rodent neonatal cardiomyocytes. The unconjugated bile acids CDCA, DCA and UDCA and, to a lesser extent, CA were found to be relatively potent agonists for the GPBAR1 (TGR5) receptor and elicit cAMP release, whereas all glyco- and tauro- conjugated bile acids are weak agonists. The bile acid-induced cAMP production does not lead to an increase in contraction rate, and seems to be mediated by the RI isoform of adenylate cyclase, unlike adrenaline-dependent release which is mediated by the RII isoform. In contrast, bile acids elicited slowing of neonatal cardiomyocyte contraction indicating that other signalling pathways are involved. The conjugated bile acids were found to be partial agonists of the muscarinic M2, but not sphingosin-1-phosphate-2, receptors, and act partially through the Gi pathway. Furthermore, the contraction slowing effect of unconjugated bile acids may also relate to cytotoxicity at higher concentrations.Effendi IbrahimIvan DiakonovDulasi ArunthavarajahTeresa SwiftMary GoodwinSaraid McIlvrideVanya NikolovaCatherine WilliamsonJulia GorelikNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Effendi Ibrahim Ivan Diakonov Dulasi Arunthavarajah Teresa Swift Mary Goodwin Saraid McIlvride Vanya Nikolova Catherine Williamson Julia Gorelik Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5
description	Abstract Bile acids are recognised as bioactive signalling molecules. While they are known to influence arrhythmia susceptibility in cholestasis, there is limited knowledge about the underlying mechanisms. To delineate mechanisms underlying fetal heart rhythm disturbances in cholestatic pregnancy, we used FRET microscopy to monitor cAMP release and contraction measurements in isolated rodent neonatal cardiomyocytes. The unconjugated bile acids CDCA, DCA and UDCA and, to a lesser extent, CA were found to be relatively potent agonists for the GPBAR1 (TGR5) receptor and elicit cAMP release, whereas all glyco- and tauro- conjugated bile acids are weak agonists. The bile acid-induced cAMP production does not lead to an increase in contraction rate, and seems to be mediated by the RI isoform of adenylate cyclase, unlike adrenaline-dependent release which is mediated by the RII isoform. In contrast, bile acids elicited slowing of neonatal cardiomyocyte contraction indicating that other signalling pathways are involved. The conjugated bile acids were found to be partial agonists of the muscarinic M2, but not sphingosin-1-phosphate-2, receptors, and act partially through the Gi pathway. Furthermore, the contraction slowing effect of unconjugated bile acids may also relate to cytotoxicity at higher concentrations.
format	article
author	Effendi Ibrahim Ivan Diakonov Dulasi Arunthavarajah Teresa Swift Mary Goodwin Saraid McIlvride Vanya Nikolova Catherine Williamson Julia Gorelik
author_facet	Effendi Ibrahim Ivan Diakonov Dulasi Arunthavarajah Teresa Swift Mary Goodwin Saraid McIlvride Vanya Nikolova Catherine Williamson Julia Gorelik
author_sort	Effendi Ibrahim
title	Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5
title_short	Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5
title_full	Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5
title_fullStr	Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5
title_full_unstemmed	Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5
title_sort	bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of gi protein, muscarinic receptors and tgr5
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/b9f80aa5866a41af9eb558fcc06bf458
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Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5

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