Figure 5.

Model of molecular mechanisms involved in Drosophila alcohol responses. Interactions (arrows) are based on our genetic and biochemical data^{19,21,25,31,40} (as well as other published data cited therein). Of particular relevance to this report: RhoGAP18B (encoded by the whir gene) binds to, and acts on Rac1.^11,40 Rac1 is linked to Arf6 via Arfaptin, which binds to either activated GTPase.²¹ Here, we show that Efa6 is required for Arf6 activation and behavioral ethanol responses, and together, these biochemical data support our initial finding of a genetic interaction between whir and Efa6, placing them in the same network. Note that all molecules depicted here have mammalian orthologs, with the exception of RhoGAP18B, which contains a GTPase activating GAP domain and long stretches without any other characterized domains. Proteins whose genes are associated with human alcohol drinking are depicted in red (Rsu1,⁴⁰ Efa6, this report), ones involved in rodent alcohol drinking in blue,^27,60 and ones linked to rodent cocaine-induced behaviors in green (Rac1,cofilin).^61,62 Abbreviations: ILK: integrin-linked kinase, PINCH: particularly interesting Cys-His rich protein, Rsu1: Ras-suppressor 1, Rac: Ras-related C3 botulinum toxin substrate, Limk1: LIM domain kinase 1, Rock: Rho-associated kinase, Arf6: ADP-ribosylation factor 6, PLD: phospholipase D, Akt: Thymona-associated kinase from the Ak strain, mTor: mechanistic target of rapamycin, S6k: S6 kinase.