Adenosine A2A receptor inhibition restores the normal transport of endothelial glutamate transporters in the brain.

Abstract

Excitatory amino acid transporters (EAATs) on cerebral vascular endothelial cells play an important role in maintaining glutamate homeostasis in the brain. The dysfunction of endothelial EAATs is an important reason for the dramatically elevated brain glutamate levels after brain injury, such as traumatic brain injury (TBI). The adenosine A2A receptor (A2AR) plays an important role in regulating the brain glutamate level after brain injury; however, researchers have not clearly determined whether this role was related to its ability to regulate endothelial EAATs. Activation of A2AR in vitro not only decreased the PKA- and glutamate level-dependent strengthening of the interaction between NKA-α1 and the FXYD1 subunit and the subsequent decrease in the activity of Na+/K+-ATPases (NKAs) but also enhanced its interaction with EAATs and ultimately aggravated the reverse transport function of endothelial EAATs under oxygen-glucose deprivation (OGD) conditions. Conversely, inhibition of A2AR restored the normal transport of EAAT. Moreover, A2AR inhibition increased NKA activity and decreased its interaction with EAATs in isolated brain capillaries after TBI, further confirming its role in endothelial EAATs in vivo. Based on our results, A2AR played an important role in regulating endothelial EAAT function, and strategies that restore the normal transport of endothelial EAATs through the inhibition of A2AR might serve as an effective treatment for brain injury.

• Authors: Wei Bai, Ping Li, Ya-Lei Ning, Yan Peng, Ren-Ping Xiong, Nan Yang, Xing Chen, Yuan-Guo Zhou
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 498 Issue 4 Pg. 795-802 (04 15 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 29526759 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Adenosine A2 Receptor Agonists
• Adenosine A2 Receptor Antagonists
• Glutamate Plasma Membrane Transport Proteins
• Receptor, Adenosine A2A
• Glutamic Acid
• Sodium-Potassium-Exchanging ATPase

Topics

• Adenosine A2 Receptor Agonists (pharmacology)
• Adenosine A2 Receptor Antagonists (pharmacology)
• Animals
• Brain (drug effects, metabolism)
• Brain Injuries, Traumatic (drug therapy, genetics, metabolism)
• Endothelium (drug effects, metabolism)
• Glutamate Plasma Membrane Transport Proteins (metabolism)
• Glutamic Acid (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Receptor, Adenosine A2A (genetics, metabolism)
• Sodium-Potassium-Exchanging ATPase (metabolism)