Instituto de Investigação e Inovação em Saúde (i3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.
Free Radic Biol Med. 2021 Feb 1;163:43-55. doi: 10.1016/j.freeradbiomed.2020.11.039. Epub 2020 Dec 8.
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.
腺苷是中枢神经系统中的一种重要神经调质，调节神经元存活和突触传递。抗氧化剂抗坏血酸（维生素 C 的还原形式）通过一种名为 SVCT2 的钠离子依赖性转运体在中枢神经系统神经元中浓缩，并参与多种中枢神经系统过程，例如调节谷氨酸受体功能和神经调质的合成。在这里，我们研究了中枢神经系统中腺苷能系统和抗坏血酸转运之间的相互作用。我们发现，选择性激活 A3 而非 A1 或 A2a 腺苷受体可调节抗坏血酸转运，减少细胞内抗坏血酸含量。荧光共振能量转移（FRET）分析表明，A3 受体与抗坏血酸转运体 SVCT2 相关，表明 A3 受体和 SVCT2 之间存在紧密的信号分隔。A3 受体的激活以 SVCT2 依赖的方式增加抗坏血酸的释放，这在不干扰细胞死亡、糖酵解代谢和生物能量的情况下，极大地改变了神经元的氧化还原状态。总的来说，通过调节维生素 C 转运，腺苷能系统（通过激活 A3 受体）可以调节抗坏血酸的生物利用度并控制神经元中的氧化还原平衡。
