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-DOPAquinone 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 preopen conformation through formation of a covalent adduct with cysteine-65 that L-DOPA-quinone stabilizes GIRK in on the GIRK2 subunit of the protein.
Bizzarri, B.m., Botta, L., Aversa, D., Mercuri, N.b., Poli, G., Barbieri, A., et al. (2019). L-DOPA-quinone Mediated Recovery from GIRK Channel Firing Inhibition in Dopaminergic Neurons. ACS MEDICINAL CHEMISTRY LETTERS, 10(4), 431-436 [10.1021/acsmedchemlett.8b00477].
L-DOPA-quinone Mediated Recovery from GIRK Channel Firing Inhibition in Dopaminergic Neurons
Botta L.;Mercuri N. B.;
2019-01-01
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-DOPAquinone 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 preopen conformation through formation of a covalent adduct with cysteine-65 that L-DOPA-quinone stabilizes GIRK in on the GIRK2 subunit of the protein.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
