Dopamine Modulates Drosophila Gut Physiology, Providing New Insights for Future Gastrointestinal Pharmacotherapy

SIMPLE SUMMARY: Dopamine is involved in a variety of physiological functions in the gastrointestinal tract (GI). Using a Drosophila model, we investigated the effects of dopamine administration on intestinal physiology and gut motility to gain new insights into what could be a potential future promise candidate for GI pharmacology. We investigated whether giving a dopamine-supplemented food medium to adult flies modified the gut contents, defecation rate, and excreta nature. The effects of dopamine on adult gut spontaneous contraction and motility were also studied. We discovered significant gender differences in the effect of dopamine. Drosophila dopamine D1-like receptors (Dop1R1 and Dop1R2) were also displayed by immunohistochemistry to be expressed in all smooth muscles in both larval and adult flies. Furthermore, we showed for the first time that dopamine drives phospholipase C Beta (PLC-β) translocation from the cytoplasm to the plasma membrane in enterocytes. Overall, the data provided new insights into the epidemiology and clinical aspects of neurodegenerative diseases associated with dopamine deficiency, as well as what may be a potential future prospect for GI pharmacotherapy. ABSTRACT: Dopamine has a variety of physiological roles in the gastrointestinal tract (GI) through binding to Drosophila dopamine D1-like receptors (DARs) and/or adrenergic receptors and has been confirmed as one of the enteric neurotransmitters. To gain new insights into what could be a potential future promise for GI pharmacology, we used Drosophila as a model organism to investigate the effects of dopamine on intestinal physiology and gut motility. GAL4/UAS system was utilized to knock down specific dopamine receptors using specialized GAL4 driver lines targeting neurons or enterocytes cells to identify which dopamine receptor controls stomach contractions. DARs (Dop1R1 and Dop1R2) were shown by immunohistochemistry to be strongly expressed in all smooth muscles in both larval and adult flies, which could explain the inhibitory effect of dopamine on GI motility. Adult males’ gut peristalsis was significantly inhibited by knocking down dopamine receptors Dop1R1, Dop1R2, and Dop2R, but female flies’ gut peristalsis was significantly repressed by knocking down only Dop1R1 and Dop1R2. Our findings also showed that dopamine drives PLC-β translocation from the cytoplasm to the plasma membrane in enterocytes for the first time. Overall, these data revealed the role of dopamine in modulating Drosophila gut physiology, offering us new insights for the future gastrointestinal pharmacotherapy of neurodegenerative diseases associated with dopamine deficiency.