An Unrecognized Fundamental Relationship between Neurotransmitters: Glutamate Protects against Catecholamine Oxidation

Abstract

Neurotransmitter catecholamines (dopamine, epinephrine, and norepinephrine) are liable to undergo oxidation, which copper is deeply involved in. Catecholamine oxidation-derived neurotoxicity is recognized as a pivotal pathological mechanism in neurodegenerative diseases. Glutamate, as an excitatory neurotransmitter, is enriched in the brain at extremely high concentrations. However, the chemical biology relationship of these two classes of neurotransmitters remains largely unknown. In the present study, we assessed the influences of glutamate on the autoxidation of catecholamines, the copper- and copper-containing ceruloplasmin-mediated oxidation of catecholamines, the catecholamine-induced formation of quinoprotein, catecholamine/copper-induced hydroxyl radicals, and DNA damage in vitro. The results demonstrate that glutamate, at a physiologically achievable molar ratio of glutamate/catecholamines, has a pronounced inhibitory effect on catecholamine oxidation, catecholamine oxidation-evoked hydroxyl radicals, quinoprotein, and DNA damage. The protective mechanism of glutamate against catecholamine oxidation could be attributed to its restriction of the redox activity of copper via chelation. This previously unrecognized link between glutamate, catecholamines, and copper suggests that neurodegenerative disorders may occur and develop once the built-in equilibrium is disrupted and brings new insight into developing more effective prevention and treatment strategies for neurodegenerative diseases.

l-Theanine Inhibits (−)-Epigallocatechin-3-gallate Oxidation via Chelating Copper

“…Thus, the previous proposal that l -theanine could be hydrolyzed into glutamate in the intestine and liver has no solid evidence. The observed role of l -theanine in pro-oxidant actions of EGCG implies that glutamate may participate in reducing pro-oxidant properties of EGCG because it has been found that glutamate can inhibit dopamine oxidation via chelating copper . However, glutamate is not a suitable supplemental agent for reducing the pro-oxidant role of EGCG because individuals who consume elevated amounts of monosodium glutamate in their diet are more likely to suffer from headaches and short-term elevated blood pressure. , …”

“…As shown in Figure 1a, 50 mM copper sulfate solution exhibited a light blue color, and the addition of L-theanine at a molar ratio of 1−10 (L-theanine/divalent copper) dose-dependently enhanced the blue color, demonstrating that L-theanine, like its structural analogue glutamic acid or glutamate, formed a complex with copper. 14,19 EGCG is liable to autoxidation in neutral to alkaline environments; 8,19 however, the autoxidation of EGCG alone is trivial at pH 6.0 as reflected by OD 410nm values (Figure 1b). Under this circumstance, divalent copper ions greatly enhanced EGCG oxidation (Figure 1b).…”

“…Catecholamines including dopamine, epinephrine, and norepinephrine in the brain are neurotransmitters. Our group recently revealed that glutamate as a neurotransmitter exhibits pronounced inhibitory activity against catecholamine oxidation via chelating and restraining redox activity of copper . Specifically, autoxidation of catecholamines and copper-facilitated oxidation of catecholamines can be suppressed by glutamate, ROS production due to catecholamine autoxidation and hydroxyl radical formation or DNA damage due to copper-mediated catecholamine oxidation can be inhibited by glutamate, and the protein–quinone adduct known as quinoprotein can be reduced by glutamate due to catecholamine oxidation.…”

“…Our group recently revealed that glutamate as a neurotransmitter exhibits pronounced inhibitory activity against catecholamine oxidation via chelating and restraining redox activity of copper. 14 Specifically, autoxidation of catecholamines and copperfacilitated oxidation of catecholamines can be suppressed by glutamate, ROS production due to catecholamine autoxidation and hydroxyl radical formation or DNA damage due to coppermediated catecholamine oxidation can be inhibited by glutamate, and the protein−quinone adduct known as quinoprotein can be reduced by glutamate due to catecholamine oxidation. Although high concentrations of glutamate are required to restrain the pro-oxidant activity of copper and prevent catecholamine oxidation, the brain and dopaminergic neurons were evolutionally endowed with exceptionally abundant intracellular glutamate (as high as 10 mM).…”

Oxidative Stress in Neurodegenerative Diseases

“…Wang W. et al report interesting and original new observations regarding the crosstalk between the excitatory neurotransmitter glutamate and dopamine oxidation [3]. This study identifies several mechanisms by which glutamate might regulate dopamine oxidation, a process that is recognized to have a toxic impact in Parkinson's disease (PD).…”