Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol
AffiliationUniv Arizona, Coll Pharm, Dept Pharmacol & Toxicol
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PublisherNATURE PUBLISHING GROUP
CitationStructural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol 2017, 7 (1) Scientific Reports
Rights© The Author(s) 2017. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License.
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AbstractMitochondrial dysfunction is associated with numerous acute and chronic degenerative diseases. The beta-2 adrenergic receptor (beta(2)AR) agonist formoterol induces mitochondrial biogenesis (MB), but other beta(2)AR 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 G beta gamma- and PI3K-dependent, and the increase in eNOS phosphorylation was G beta gamma- and Akt-dependent. Only formoterol increased cGMP. Formoterol induced MB as measured by increases in uncoupled cellular respiration and PGC-1 alpha and NDUFS1 mRNA expression and was blocked by inhibitors of G beta gamma, 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 beta(2)AR. 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 beta(2)AR to activate the G beta gamma-Akt-eNOS-sGC pathway to induce MB.
VersionFinal published version
SponsorsNational Institutes of Health [F30 DK104550, T32 GM008716, T32 HL007260, P20 GM103542, R01 GM084147]; Department of Veterans Affairs [1BX000851]