TRPM6 and TRPM7 differentially contribute to the relief of heteromeric TRPM6/7 channels from inhibition by cytosolic Mg2+ and Mg·ATP

Abstract TRPM6 and its homologue TRPM7 are α-kinase-coupled divalent cation-selective channels activated upon reduction of cytosolic levels of Mg2+ and Mg·ATP. TRPM6 is vital for organismal Mg2+ balance. However, mechanistically the cellular role and functional nonredundancy of TRPM6 remain incomple...

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Autores principales:	Silvia Ferioli, Susanna Zierler, Joanna Zaißerer, Johann Schredelseker, Thomas Gudermann, Vladimir Chubanov
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ed61a16c849844f1ac78a313b8afcf6c
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spelling	oai:doaj.org-article:ed61a16c849844f1ac78a313b8afcf6c2021-12-02T11:40:58ZTRPM6 and TRPM7 differentially contribute to the relief of heteromeric TRPM6/7 channels from inhibition by cytosolic Mg2+ and Mg·ATP10.1038/s41598-017-08144-12045-2322https://doaj.org/article/ed61a16c849844f1ac78a313b8afcf6c2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08144-1https://doaj.org/toc/2045-2322Abstract TRPM6 and its homologue TRPM7 are α-kinase-coupled divalent cation-selective channels activated upon reduction of cytosolic levels of Mg2+ and Mg·ATP. TRPM6 is vital for organismal Mg2+ balance. However, mechanistically the cellular role and functional nonredundancy of TRPM6 remain incompletely understood. Comparative analysis of native currents in primary cells from TRPM6- versus TRPM7-deficient mice supported the concept that native TRPM6 primarily functions as a constituent of heteromeric TRPM6/7 channels. However, heterologous expression of the human TRPM6 protein engendered controversial results with respect to channel characteristics including its regulation by Mg2+ and Mg·ATP. To resolve this issue, we cloned the mouse TRPM6 (mTRPM6) cDNA and compared its functional characteristics to mouse TRPM7 (mTRPM7) after heterologous expression. Notably, we observed that mTRPM6 and mTRPM7 differentially regulate properties of heteromeric mTRPM6/7 channels: In the presence of mTRPM7, the extreme sensitivity of functionally expressed homomeric mTRPM6 to Mg2+ is tuned to higher concentrations, whereas mTRPM6 relieves mTRPM7 from the tight inhibition by Mg·ATP. Consequently, the association of mTRPM6 with mTRPM7 allows for high constitutive activity of mTRPM6/7 in the presence of physiological levels of Mg2+ and Mg·ATP, thus laying the mechanistic foundation for constant vectorial Mg2+ transport specifically into epithelial cells.Silvia FerioliSusanna ZierlerJoanna ZaißererJohann SchredelsekerThomas GudermannVladimir ChubanovNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-19 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Silvia Ferioli Susanna Zierler Joanna Zaißerer Johann Schredelseker Thomas Gudermann Vladimir Chubanov TRPM6 and TRPM7 differentially contribute to the relief of heteromeric TRPM6/7 channels from inhibition by cytosolic Mg2+ and Mg·ATP
description	Abstract TRPM6 and its homologue TRPM7 are α-kinase-coupled divalent cation-selective channels activated upon reduction of cytosolic levels of Mg2+ and Mg·ATP. TRPM6 is vital for organismal Mg2+ balance. However, mechanistically the cellular role and functional nonredundancy of TRPM6 remain incompletely understood. Comparative analysis of native currents in primary cells from TRPM6- versus TRPM7-deficient mice supported the concept that native TRPM6 primarily functions as a constituent of heteromeric TRPM6/7 channels. However, heterologous expression of the human TRPM6 protein engendered controversial results with respect to channel characteristics including its regulation by Mg2+ and Mg·ATP. To resolve this issue, we cloned the mouse TRPM6 (mTRPM6) cDNA and compared its functional characteristics to mouse TRPM7 (mTRPM7) after heterologous expression. Notably, we observed that mTRPM6 and mTRPM7 differentially regulate properties of heteromeric mTRPM6/7 channels: In the presence of mTRPM7, the extreme sensitivity of functionally expressed homomeric mTRPM6 to Mg2+ is tuned to higher concentrations, whereas mTRPM6 relieves mTRPM7 from the tight inhibition by Mg·ATP. Consequently, the association of mTRPM6 with mTRPM7 allows for high constitutive activity of mTRPM6/7 in the presence of physiological levels of Mg2+ and Mg·ATP, thus laying the mechanistic foundation for constant vectorial Mg2+ transport specifically into epithelial cells.
format	article
author	Silvia Ferioli Susanna Zierler Joanna Zaißerer Johann Schredelseker Thomas Gudermann Vladimir Chubanov
author_facet	Silvia Ferioli Susanna Zierler Joanna Zaißerer Johann Schredelseker Thomas Gudermann Vladimir Chubanov
author_sort	Silvia Ferioli
title	TRPM6 and TRPM7 differentially contribute to the relief of heteromeric TRPM6/7 channels from inhibition by cytosolic Mg2+ and Mg·ATP
title_short	TRPM6 and TRPM7 differentially contribute to the relief of heteromeric TRPM6/7 channels from inhibition by cytosolic Mg2+ and Mg·ATP
title_full	TRPM6 and TRPM7 differentially contribute to the relief of heteromeric TRPM6/7 channels from inhibition by cytosolic Mg2+ and Mg·ATP
title_fullStr	TRPM6 and TRPM7 differentially contribute to the relief of heteromeric TRPM6/7 channels from inhibition by cytosolic Mg2+ and Mg·ATP
title_full_unstemmed	TRPM6 and TRPM7 differentially contribute to the relief of heteromeric TRPM6/7 channels from inhibition by cytosolic Mg2+ and Mg·ATP
title_sort	trpm6 and trpm7 differentially contribute to the relief of heteromeric trpm6/7 channels from inhibition by cytosolic mg2+ and mg·atp
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ed61a16c849844f1ac78a313b8afcf6c
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TRPM6 and TRPM7 differentially contribute to the relief of heteromeric TRPM6/7 channels from inhibition by cytosolic Mg2+ and Mg·ATP

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