Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol

Abstract Mitochondrial dysfunction is associated with numerous acute and chronic degenerative diseases. The beta-2 adrenergic receptor (β2AR) agonist formoterol induces mitochondrial biogenesis (MB), but other β2AR agonists, such as clenbuterol, do not. We sought to identify the MB signaling pathway...

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Autores principales:	Robert B. Cameron, Yuri K. Peterson, Craig C. Beeson, Rick G. Schnellmann
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8b2addff23fe41f2a5df5b8a3510a7ca
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spelling	oai:doaj.org-article:8b2addff23fe41f2a5df5b8a3510a7ca2021-12-02T15:05:08ZStructural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol10.1038/s41598-017-11030-52045-2322https://doaj.org/article/8b2addff23fe41f2a5df5b8a3510a7ca2017-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-11030-5https://doaj.org/toc/2045-2322Abstract Mitochondrial dysfunction is associated with numerous acute and chronic degenerative diseases. The beta-2 adrenergic receptor (β2AR) agonist formoterol induces mitochondrial biogenesis (MB), but other β2AR agonists, such as clenbuterol, do not. We sought to identify the MB signaling pathway of formoterol and the differences in signaling between these two ligands that result in the differential induction of MB. While formoterol and clenbuterol increased cAMP, only formoterol increased the phosphorylation of Akt and its downstream target eNOS. The increase in Akt phosphorylation was Gβγ- and PI3K-dependent, and the increase in eNOS phosphorylation was Gβγ- and Akt-dependent. Only formoterol increased cGMP. Formoterol induced MB as measured by increases in uncoupled cellular respiration and PGC-1α and NDUFS1 mRNA expression and was blocked by inhibitors of Gβγ, Akt, NOS, and soluble guanylate cyclase. To identify distinct receptor-ligand interactions leading to these differences in signaling, we docked formoterol and clenbuterol to six structures of the β2AR. Compared to clenbuterol, the methoxyphenyl group of formoterol interacted more frequently with V114 and F193, while its formamide group interacted more frequently with C191. These data indicate that the unique structural features of formoterol allow it to interact with the β2AR to activate the Gβγ-Akt-eNOS-sGC pathway to induce MB.Robert B. CameronYuri K. PetersonCraig C. BeesonRick G. SchnellmannNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Robert B. Cameron Yuri K. Peterson Craig C. Beeson Rick G. Schnellmann Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol
description	Abstract Mitochondrial dysfunction is associated with numerous acute and chronic degenerative diseases. The beta-2 adrenergic receptor (β2AR) agonist formoterol induces mitochondrial biogenesis (MB), but other β2AR agonists, such as clenbuterol, do not. We sought to identify the MB signaling pathway of formoterol and the differences in signaling between these two ligands that result in the differential induction of MB. While formoterol and clenbuterol increased cAMP, only formoterol increased the phosphorylation of Akt and its downstream target eNOS. The increase in Akt phosphorylation was Gβγ- and PI3K-dependent, and the increase in eNOS phosphorylation was Gβγ- and Akt-dependent. Only formoterol increased cGMP. Formoterol induced MB as measured by increases in uncoupled cellular respiration and PGC-1α and NDUFS1 mRNA expression and was blocked by inhibitors of Gβγ, Akt, NOS, and soluble guanylate cyclase. To identify distinct receptor-ligand interactions leading to these differences in signaling, we docked formoterol and clenbuterol to six structures of the β2AR. Compared to clenbuterol, the methoxyphenyl group of formoterol interacted more frequently with V114 and F193, while its formamide group interacted more frequently with C191. These data indicate that the unique structural features of formoterol allow it to interact with the β2AR to activate the Gβγ-Akt-eNOS-sGC pathway to induce MB.
format	article
author	Robert B. Cameron Yuri K. Peterson Craig C. Beeson Rick G. Schnellmann
author_facet	Robert B. Cameron Yuri K. Peterson Craig C. Beeson Rick G. Schnellmann
author_sort	Robert B. Cameron
title	Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol
title_short	Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol
title_full	Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol
title_fullStr	Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol
title_full_unstemmed	Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol
title_sort	structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8b2addff23fe41f2a5df5b8a3510a7ca
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Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol

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