Coronaridine congeners modulate mitochondrial α3ß4* nicotinic acetylcholine receptors with different potency and through distinct intra-mitochondrial pathways.
Neurochem Int
; 114: 26-32, 2018 03.
Article
em En
| MEDLINE
| ID: mdl-29277577
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 α3ß4* 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 α3ß4* 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 α3ß4* nAChR signaling, giving a more comprehensive understanding on the function of intracellular nAChR subtypes.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Mitocôndrias Hepáticas
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Transdução de Sinais
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Receptores Nicotínicos
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Ibogaína
Limite:
Animals
Idioma:
En
Revista:
Neurochem Int
Ano de publicação:
2018
Tipo de documento:
Article