Mechanism of Purinergic Regulation of Neurotransmission in Mouse Neuromuscular Junction: The Role of Redox Signaling and Lipid Rafts.

Autor: Giniatullin AR; Kazan State Medical University, 49 Butlerova St., Kazan, RT, Russia, 420012. arthur.giniyatullin@kazangmu.ru., Mukhutdinova KA; Kazan State Medical University, 49 Butlerova St., Kazan, RT, Russia, 420012.; Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, 2/31 Lobachevsky St, Kazan, RT, Russia, 420111., Petrov AM; Kazan State Medical University, 49 Butlerova St., Kazan, RT, Russia, 420012. alexey.petrov@kazangmu.ru.; Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, 2/31 Lobachevsky St, Kazan, RT, Russia, 420111. alexey.petrov@kazangmu.ru.; Kazan Federal University, 18 Kremlyovskaya Street, Kazan, Russia, 420008. alexey.petrov@kazangmu.ru.
Jazyk: angličtina
Zdroj: Neurochemical research [Neurochem Res] 2024 Aug; Vol. 49 (8), pp. 2021-2037. Date of Electronic Publication: 2024 May 30.
DOI: 10.1007/s11064-024-04153-5
Abstrakt: Acetylcholine is the main neurotransmitter at the vertebrate neuromuscular junctions (NMJs). ACh exocytosis is precisely modulated by co-transmitter ATP and its metabolites. It is assumed that ATP/ADP effects on ACh release rely on activation of presynaptic G i protein-coupled P 2 Y 13 receptors. However, downstream signaling mechanism of ATP/ADP-mediated modulation of neuromuscular transmission remains elusive. Using microelectrode recording and fluorescent indicators, the mechanism underlying purinergic regulation was studied in the mouse diaphragm NMJs. Pharmacological stimulation of purinoceptors with ADP decreased synaptic vesicle exocytosis evoked by both low and higher frequency stimulation. This inhibitory action was suppressed by antagonists of P 2 Y 13 receptors (MRS 2211), Ca 2+ mobilization (TMB8), protein kinase C (chelerythrine) and NADPH oxidase (VAS2870) as well as antioxidants. This suggests the participation of Ca 2+ and reactive oxygen species (ROS) in the ADP-triggered signaling. Indeed, ADP caused an increase in cytosolic Ca 2+ with subsequent elevation of ROS levels. The elevation of [Ca 2+ ] in was blocked by MRS 2211 and TMB8, whereas upregulation of ROS was prevented by pertussis toxin (inhibitor of G i protein) and VAS2870. Targeting the main components of lipid rafts, cholesterol and sphingomyelin, suppressed P 2 Y 13 receptor-dependent attenuation of exocytosis and ADP-induced enhancement of ROS production. Inhibition of P 2 Y 13 receptors decreased ROS production and increased the rate of exocytosis during intense activity. Thus, suppression of neuromuscular transmission by exogenous ADP or endogenous ATP can rely on P 2 Y 13 receptor/G i protein/Ca 2+ /protein kinase C/NADPH oxidase/ROS signaling, which is coordinated in a lipid raft-dependent manner.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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