Integral membrane protein, anchor, is expressed in the Drosophila insulin-producing cells and is a novel modulator of homeostatic behaviors, including sleep, feeding, and sedation

Abstract

Integral membrane proteins (IMPs) are central regulators of cellular signaling and represent a major class of therapeutic targets. GPR155 (also known as LYCHOS), an evolutionarily conserved protein containing both transporter-like and GPCR-like domains, has recently emerged as a lysosomal nutrient sensor implicated in mTORC1 signaling. Despite its enriched expression in brain regions associated with reward processing, the in vivo neuronal and behavioral functions of GPR155 remain undefined. Here, we leverage the genetic tractability of Drosophila melanogaster to characterize the role of the GPR155 ortholog, anchor, in neural circuit function and behavior. Here, we demonstrate that pan-neuronal downregulation of anchor leads to significant alterations in multiple behaviors, including reduced feeding, disrupted light-dependent rhythmicity, decreased sleep, increased waking locomotor activity, and diminished sedation sensitivity to ethanol. We also selectively manipulated anchor expression in the neuroendocrine insulin-producing cells (IPCs), which phenocopied impaired rhythmicity and decreased ethanol sedation sensitivity observed in pan-neuronal manipulations, indicating that anchor function within IPCs is sufficient to modulate discrete behavioral outputs. Our results suggest that anchor regulates behavior in a sexually dimorphic manner as changes in ethanol sedation sensitivity were more penetrant in females, whereas altered feeding and ethanol preference was observed only in males. These findings establish a previously unrecognized role for anchor in the regulation of neuroendocrine signaling and behavior. Given the conservation of mTORC1 signaling and neuropeptidergic systems across species, this work provides mechanistic insight into how multifunctional IMPs integrate metabolic and environmental cues to influence complex behaviors, with potential implications for understanding the molecular basis of feeding, sleep regulation, and substance use disorders.