The dual-site agonist for human M2 muscarinic receptors Iper-8-naphtalimide induces mitochondrial dysfunction in Saccharomyces cerevisiae

Glioblastoma is a malignant astrocytic tumor of the brain. A significantly decrease of glioblastoma cell proliferation and survival can be achieved by activating the M2 muscarinic acetylcholine receptor (a G protein-coupled receptor, or GPCR) with two agonist molecules, the orthosteric agonist Arecaidine Propargyl Ester (APE) and the dualsteric agonist Iper-8-naphthalimide (N-8-Iper). In glioblastoma cells, these agonists caused mitochondrial damage and an altered lipid profile. To characterize the mitochondrial dysfunction induced by the muscarinic agonists, we tested APE and N-8-Iper in S. cerevisiae, a yeast model system specifically suitable to study the activity of molecules of pharmaceutical interest on mitochondria. N-8-Iper, but not APE, induced mitochondrial dysfunction in S. cerevisiae cells in a time- and concentration-dependent manner. These results suggest that the agonist N-8-Iper on glioblastoma cell cultures has a direct effect on mitochondrial function. Moreover, since GPCRs are evolutionarily conserved from yeast to humans, these results confirm that the yeast system is a suitable model for studying human GPCRs.