Activation of adenosine A3 receptors regulates vitamin C transport and redox balance in neurons

Adenosine is an important neuromodulator in the CNS, regulating neuronal survival and synaptic transmission. The antioxidant ascorbate (the reduced form of vitamin C) is concentrated in CNS neurons through a sodium-dependent transporter named SVCT2 and participates in several CNS processes, for inst...

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Published in:	Free radical biology & medicine Vol. 163; pp. 43 - 55
Main Authors:	Portugal, Camila C., da Encarnação, Thaísa G., Sagrillo, Mayara A., Pereira, Mariana R., Relvas, João B., Socodato, Renato, Paes-de-Carvalho, Roberto
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-02-2021
Subjects:	Ascorbate Oxidative signaling Purinergic signaling Reactive oxygen species (ROS) Retina SVCT2 Transporter reversion SVCT2 Reactive oxygen species (ROS) Retina Ascorbate Oxidative signaling Transporter reversion Purinergic signaling
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Summary:	Adenosine is an important neuromodulator in the CNS, regulating neuronal survival and synaptic transmission. The antioxidant ascorbate (the reduced form of vitamin C) is concentrated in CNS neurons through a sodium-dependent transporter named SVCT2 and participates in several CNS processes, for instance, the regulation of glutamate receptors functioning and the synthesis of neuromodulators. Here we studied the interplay between the adenosinergic system and ascorbate transport in neurons. We found that selective activation of A3, but not of A1 or A2a, adenosine receptors modulated ascorbate transport, decreasing intracellular ascorbate content. Förster resonance energy transfer (FRET) analyses showed that A3 receptors associate with the ascorbate transporter SVCT2, suggesting tight signaling compartmentalization between A3 receptors and SVCT2. The activation of A3 receptors increased ascorbate release in an SVCT2-dependent manner, which largely altered the neuronal redox status without interfering with cell death, glycolytic metabolism, and bioenergetics. Overall, by regulating vitamin C transport, the adenosinergic system (via activation of A3 receptors) can regulate ascorbate bioavailability and control the redox balance in neurons. [Display omitted] •Adenosine controls vitamin C bioavailability by regulating ascorbate transport.•Activation of adenosine A3 receptors increases ascorbate release diminishing intracellular ascorbate content.•A3R-induced ascorbate release leads to ROS accumulation in neurons.•Adenosine, via A3R and ascorbate transport, regulates the neuronal redox balance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0891-5849 1873-4596
DOI:	10.1016/j.freeradbiomed.2020.11.039