Coronaridine congeners modulate mitochondrial α3β4* nicotinic acetylcholine receptors with different potency and through distinct intra-mitochondrial pathways

Hugo R. Arias, Olena Lykhmus, Kateryna Uspenska, Maryna Skok

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3 Scopus citations

Abstract

In contrast to plasma membrane-expressed nicotinic acetylcholine receptors (nAChRs), mitochondrial nAChRs function in an ion-independent manner by triggering intra-mitochondrial kinases that regulate the release of cytochrome c (Cyt c), an important step in cellular apoptosis. The aim of this study is to determine the structural requirements for mitochondrial α3β4* nAChR activation by measuring the modulatory effects of two noncompetitive antagonists of these receptors, (+)-catharanthine and (±)-18-methoxycoronaridine [(±)-18-MC], on Cyt c release from wild-type and α7−/− mice mitochondria. The sandwich ELISA results indicated that α3β4* nAChRs are present in liver mitochondria in higher amounts compared to that in brain mitochondria and that these receptors are up-regulated in α7−/− mice. Correspondingly, (±)-18-MC decreased Cyt c release from liver mitochondria of wild-type mice and from brain and liver mitochondria of α7−/− mice. The effect in wild-type mice mitochondria was mediated mainly by the Src-dependent pathway, regulating the apoptogenic activity of reactive oxygen species, while in α7−/− mice mitochondria, (±)-18-MC strongly affected the calcium-calmodulin kinase II-dependent pathway. In contrast, (+)-catharanthine was much less potent than (±)-18-MC and triggered several signaling pathways, suggesting the involvement of multiple nAChR subtypes. These results show for the first time that noncompetitive antagonists can induce mitochondrial α3β4* nAChR signaling, giving a more comprehensive understanding on the function of intracellular nAChR subtypes.

Original languageEnglish
Pages (from-to)26-32
Number of pages7
JournalNeurochemistry International
Volume114
DOIs
Publication statusPublished - 1 Mar 2018
Externally publishedYes

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Keywords

  • (+)-Catharanthine
  • (±)-18-Methoxycoronaridine
  • Coronaridine congeners
  • Mitochondria-driven apoptosis
  • Mitochondrial nicotinic acetylcholine receptors

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