moody Encodes Two GPCRs that Regulate Cocaine Behaviors and Blood-Brain Barrier Permeability in Drosophila

• Published in: Cell 2005-10, Vol.123 (1), p.145-156
• Main Authors: Bainton, Roland J., Tsai, Linus T.-Y., Schwabe, Tina, DeSalvo, Michael, Gaul, Ulrike, Heberlein, Ulrike
• Format: Article
• Language: English
• Subjects: Alternative Splicing - genetics; Animals; Behavior, Animal - drug effects; Behavior, Animal - physiology; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain - drug effects; Brain - metabolism; Cocaine - pharmacology; Cocaine-Related Disorders - genetics; Cocaine-Related Disorders - metabolism; Disease Models, Animal; Dopamine Uptake Inhibitors - pharmacology; Drosophila; Drosophila melanogaster - drug effects; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - isolation & purification; Drosophila Proteins - metabolism; Drug Tolerance - genetics; Male; Motor Activity - drug effects; Motor Activity - physiology; Neuroglia - cytology; Neuroglia - metabolism; Nicotine - pharmacology; Protein Structure, Tertiary - genetics; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - isolation & purification; Receptors, G-Protein-Coupled - metabolism; Substance-Related Disorders - genetics
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2005.07.029

We identified moody in a genetic screen for Drosophila mutants with altered cocaine sensitivity. Hypomorphic mutations in moody cause an increased sensitivity to cocaine and nicotine exposure. In contrast, sensitivity to the acute intoxicating effects of ethanol is reduced. The moody locus encodes two novel GPCRs, Moody-α and Moody-β. While identical in their membrane-spanning domains, the two Moody proteins differ in their long carboxy-terminal domains, which are generated by use of alternative reading frames. Both Moody forms are required for normal cocaine sensitivity, suggesting that they carry out distinct but complementary functions. Moody-α and Moody-β are coexpressed in surface glia that surround the nervous system, where they are actively required to maintain the integrity of the blood-brain barrier in the adult fly. We propose that a Moody-mediated signaling pathway functions in glia to regulate nervous system insulation and drug-related behaviors.