PT545. The Direct Protein-Protein Interaction between Dopamine Transporter and Dopamine D2 Receptor: A Novel Target Site to Modulate Synaptic Dopamine
Bibliographic record
Abstract
Abstract Background: Dopamine level is strictly regulated at the synaptic level because a slight alteration can lead to severe neurological and neuropsychiatric consequences1. Dopamine transporter (DAT), which facilitates the reuptake of extracellular dopamine, used to be the sole component of regulating synaptic dopamine level. However, our previous discovery of a direct protein-protein interaction between DAT and presynaptic dopamine D2 receptor (D2R) revealed that this protein complex enables D2R to recruit extra intracellular DAT to the membrane surface and enhance dopamine reuptake2. Despite we uncovered this novel target for modulating dopaminergic tone, its effects at the behavioural level remain elusive. Methods: Male Sprague-Dawley rats were used in all three experiments. To examine the effects of D2R-DAT disruption on locomotion, normal rats and dopamine-depleted rats were injected intra-cranially (i.c.v.) with an interfering peptide to disrupt the interaction, and were subsequently placed in 43x43x30 cm open-field chambers to record their voluntary movements. Acute dopamine depletion was induced by two intra-peritoneal injections of α-methyl-p-tyrosine. In vivo micro-dialysis was also performed in anesthetized rats, starting from the baseline and following after a single S1 injection (i.c.v.). The extracellular level of dopamine in the nucleus accumbens core was determined by high-performance liquid chromatography. Results: The disruption of D2R-DAT complex significantly elevated the voluntary movement in both normal animals and dopamine-depleted animals (p<0.05). The data collected from in vivo micro-dialysis indicated that the disruption of DAT-D2R interaction increased the extracellular dopamine level by approximately 30% compared to baseline. Discussion: The elevation in locomotion and increase in extracellular dopamine together prompted that the D2R-DAT interaction is another valid target site for modulating dopaminergic neurotransmission. More importantly, this study showed that this DAT-D2R protein complex can be a potential therapeutic target for disorders associated with dopamine dysregulation such as Parkinson’s disease and attention deficit hyperactivity disorder3. References 1. Laruelle, M., Kegeles, L.S. & Abi-Dargham, A. Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. Ann N Y Acad Sci1003, 138–158 (2003). 2. Lee, F.J., et al. Dopamine transporter cell surface localization facilitated by a direct interaction with the dopamine D2 receptor. EMBO J26, 2127–2136 (2007). 3. German, C.L., Baladi, M.G., McFadden, L.M., Hanson, G.R. & Fleckenstein, A.E. Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease. Pharmacol Rev67, 1005–1024 (2015).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 0.003 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".