Normal Ethanol Sensitivity and Rapid Tolerance Require the G Protein Receptor Kinase 2 in Ellipsoid Body Neurons in Drosophila

• Published in: Alcoholism, clinical and experimental research clinical and experimental research, 2020-08, Vol.44 (8), p.1686-1699
• Main Authors: Kang, Yuan Yuan, Wachi, Yusuke, Engdorf, Elizabeth, Fumagalli, Emiliano, Wang, Youyou, Myers, Jennifer, Massey, Shebna, Greiss, Antony, Xu, Shiyu, Roman, Gregg
• Format: Article
• Language: English
• Subjects: Animals; Arousal; Arousal - drug effects; Arousal - genetics; Behavior, Treatment and Prevention; Brain - metabolism; Brain mapping; Central Nervous System Depressants - pharmacology; Coupled Receptor Kinase; Drosophila; Drosophila Proteins - genetics; Drug tolerance; Ellipsoid Body; Ethanol; Ethanol - pharmacology; Ethanol Sensitivity; G Protein; G-Protein-Coupled Receptor Kinase 2 - genetics; Gene Knockout Techniques; Hyperactivity; Insects; Locomotion; Locomotion - drug effects; Locomotion - genetics; Loss of Function Mutation; Mutation; Neuronal Plasticity - drug effects; Neuronal Plasticity - genetics; Neurons - metabolism; Original; Proteins; Rapid Tolerance; Reflex, Righting - drug effects; Righting reflex; Sleep; Sleep - drug effects; Sleep - genetics; Synaptic plasticity
• ISSN: 0145-6008; 1530-0277; 1530-0277
• DOI: 10.1111/acer.14396

Background G protein signaling pathways are key neuromodulatory mechanisms for behaviors and neurological functions that affect the impact of ethanol (EtOH) on locomotion, arousal, and synaptic plasticity. Here, we report a novel role for the Drosophila G protein–coupled receptor kinase 2 (GPRK2) as a member of the GRK4/5/6 subfamily in modulating EtOH‐induced behaviors. Methods We studied the requirement of Drosophila Gprk2 for naïve sensitivity to EtOH sedation and ability of the fly to develop rapid tolerance after a single exposure to EtOH, using the loss of righting reflex (LORR) and fly group activity monitor (FlyGrAM) assays. Results Loss‐of‐function Gprk2 mutants demonstrate an increase in alcohol‐induced hyperactivity, reduced sensitivity to the sedative effects of EtOH, and diminished rapid tolerance after a single intoxicating exposure. The requirement for Gprk2 in EtOH sedation and rapid tolerance maps to ellipsoid body neurons within the Drosophila brain, suggesting that wild‐type Gprk2 is required for modulation of locomotion and alertness. However, even though Gprk2 loss of function leads to decreased and fragmented sleep, this change in the sleep state does not depend on Gprk2 expression in the ellipsoid body. Conclusion Our work on GPRK2 has established a role for this GRK4/5/6 subfamily member in EtOH sensitivity and rapid tolerance. Neuroplasticity is linked to alcohol use disorders (AUDs). One key mechanism of synaptic plasticity involves the regulation of G protein coupled receptors and downstream pathways. Drosophila G protein coupled receptor kinase 2 (GPRK2) is required for normal ethanol sensitivity and developing rapid tolerance after a single exposure to ethanol. This requirement is mapped to the ellipsoid body (EB) neurons, a brain region which has been linked to locomotion, sleep and arousal.