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 (?2AR) agonist formoterol induces mitochondrial biogenesis (MB), but other ?2AR 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??- and PI3K-dependent, and the increase in eNOS phosphorylation was G??- and Akt-dependent. Only formoterol increased cGMP. Formoterol induced MB as measured by increases in uncoupled cellular respiration and PGC-1? and NDUFS1 mRNA expression and was blocked by inhibitors of G??, 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 ?2AR. 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 ?2AR to activate the G??-Akt-eNOS-sGC pathway to induce MB.

SUBMITTER: Cameron RB 

PROVIDER: S-EPMC5585315 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature