A peptide disrupting the D2R-DAT interaction protects against dopamine neurotoxicity.

Abstract

Dopamine reuptake from extracellular space to cytosol leads to accumulation of dopamine, which triggers neurotoxicity in dopaminergic neurons. Previous studies have shown that both dopamine D2 receptor (D2R) and dopamine transporter (DAT) are involved in dopamine neurotoxicity. However, blockade of either D2R or DAT causes side effects due to antagonism of other physiological functions of these two proteins. We previously found that DAT can form a protein complex with D2R and its cell surface expression is facilitated via D2R-DAT interaction, which regulates dopamine reuptake and intracellular dopamine levels. Here we found that an interfering peptide (DAT-S1) disrupting the D2R-DAT interaction protects neurons against dopamine neurotoxicity, and this effect is mediated by inhibiting DAT cell surface expression and inhibiting both caspase-3 and PARP-1 cleavage. This study demonstrates the role of the D2R-DAT complex in dopamine neurotoxicity and investigated the potential mechanisms, which might help better understand the mechanisms of dopamine neurotoxicity. The peptide may provide some insights to improve treatments for dopamine neurotoxicity and related diseases, such as Parkinson's disease, as well as methamphetamine- and 3,4-methsylenedioxy methamphetamine-induced neurotoxicity.

• Authors: Ping Su, Fang Liu
• Journal: Experimental neurology (Exp Neurol) Vol. 295 Pg. 176-183 (09 2017) ISSN: 1090-2430 [Electronic] United States
• PMID: 28579325 (Publication Type: Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier Inc.

Chemical References

• Caspase Inhibitors
• DRD2 protein, human
• Dopamine Plasma Membrane Transport Proteins
• Membrane Proteins
• Neuropeptides
• Neuroprotective Agents
• Receptors, Dopamine D2
• SLC6A3 protein, human
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• CASP3 protein, human
• Caspase 3
• Dopamine

Topics

• Animals
• Caspase 3 (drug effects)
• Caspase Inhibitors (pharmacology)
• Cell Line
• Dopamine (toxicity)
• Dopamine Plasma Membrane Transport Proteins (biosynthesis, drug effects, genetics)
• Humans
• In Vitro Techniques
• Membrane Proteins (biosynthesis)
• Mice
• Neostriatum (drug effects, metabolism)
• Neurons (drug effects)
• Neuropeptides (pharmacology)
• Neuroprotective Agents (pharmacology)
• Neurotoxicity Syndromes (prevention & control)
• Poly (ADP-Ribose) Polymerase-1 (antagonists & inhibitors)
• Receptors, Dopamine D2 (biosynthesis, drug effects, genetics)