L-DOPA-quinone Mediated Recovery from GIRK Channel Firing Inhibition in Dopaminergic Neurons

Bruno M. Bizzarri, Lorenzo Botta, Daniela Aversa, Nicola B. Mercuri, Giulio Poli, Alessandro Barbieri, Nicola Berretta, Raffaele Saladino

Research output: Contribution to journalArticle

Abstract

The oxidative degeneration of dopamine-releasing (DAergic) neurons in the substantia nigra pars compacta (SNc) has attracted much interest in preclinical research, due to its involvement in Parkinson's disease manifestations. Evidence exists on the participation of quinone derivatives in mitochondrial dysfunction, alpha synuclein protein aggregation, and protein degradation. With the aim to investigate the role of L-DOPA-quinone in DAergic neuron functions, we synthesized L-DOPA-quinone by use of 2-iodoxybenzoic acid and measured its activity in recovery from dopamine-mediated firing inhibition of SNc neurons. Noteworthy, L-DOPA-quinone counteracts firing inhibition in SNc DAergic neurons caused by GIRK opening. A possible mechanism to explain the effect of L-DOPA-quinone on GIRK channel has been proposed by computational models. Overall, the study showed the possibility that L-DOPA-quinone stabilizes GIRK in a preopen conformation through formation of a covalent adduct with cysteine-65 on the GIRK2 subunit of the protein.

Original languageEnglish
Pages (from-to)431-436
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 11 2019

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Keywords

  • biological activity
  • dopaminergic neurons firing
  • GIRK channel
  • L-DOPA-quinone synthesis
  • Parkinson

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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