1. Expression of a short antibody heavy chain peptide effectively antagonizes adenosine 2A receptor in vitro and in vivo.
- Author
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Zhang ZH, Xu YW, Peng Y, Chen X, Li P, and Zhou YG
- Subjects
- Adenosine A2 Receptor Antagonists chemical synthesis, Animals, Behavior, Animal drug effects, Drug Development, HEK293 Cells, Humans, Immunoglobulin Fab Fragments pharmacology, Maze Learning drug effects, Mice, Mice, Inbred C57BL, Peptides chemical synthesis, Receptor, Adenosine A2A metabolism, Signal Transduction drug effects, Adenosine A2 Receptor Antagonists pharmacology, Antibodies, Monoclonal pharmacology, Peptides pharmacology, Receptor, Adenosine A2A drug effects
- Abstract
Background: Adenosine 2A receptor (A
2A R) is involved in many physiological and pathological functions and serves as an important drug target. Inhibition of A2A R may alleviate symptoms associated with a variety of neuropsychiatric disorders. However, the currently used A2A R antagonists have specificity limitations., Research Design and Methods: A Fab fragment (Fab2838) of an A2A R mouse monoclonal antibody can specifically bind to A2A R to form a complex and inhibit the activity of its receptor. We constructed the vector AntiA2A R, a small-molecule peptide that binds to and inhibits A2A R based on Fab2838., Results: Experiments in HEK293T cells showed that peptide AntiA2A R of 29 peptides was the most effective among the synthesized peptides in inhibiting the A2A R downstream signal cAMP/PKA/CREB. In neurons, the AntiA2A R reversed the calcium flow change induced by the A2A R agonist CGS21680 (1 μM). Furthermore, AntiA2A R expression in the mice striatum weakened the p-PKA/p-CREB signal, enhanced locomotor abilities and increased time spent in the center area in the home-cage observation experiment and increased anxiolytic behavior in the elevated-plus maze test., Conclusions: Antagonistic peptide AntiA2A R can effectively block the A2A R signaling pathway. This provides a new strategy for the specific inhibition of A2A R and provides information needed for drug development.- Published
- 2020
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