Biology subjects

Sutton, L.

Publications and source records attributed to Sutton, L..

3 recordsLinked to original sources

bioRxiv2026

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

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.

neuroscience↗

bioRxiv2026

RGS6 regulates Kappa Opioid Receptor-mediated antinociceptivebehaviors

Targeting the kappa opioid receptor (KOR) system has emerged as a potential alternative to current analgesics, however, advancing the therapeutic development of KOR requires further elucidation of its intracellular signaling events and modulators. Among these intracellular modulators, Regulators of G protein signaling (RGS) proteins act as key modulators of GPCR signaling to shape nociceptive circuits and influence pain processing. Despite this, the molecular diversity of RGS proteins that shape KOR signaling and its behavioral consequences remains largely unexplored. Here we report that RGS6, a member of the R7 RGS family, is highly expressed in nociceptive areas and modulates multiple modalities of KOR-dependent anti-nociception and nocifensive behaviors. Using global single and double knockout mouse models we show that this anti-nociceptive phenotype was highly specific to RGS6 within the R7 RGS family. Further we demonstrate that the R7 RGS family displays a lack of functional redundancy in regulation of KOR signaling and behaviors. Using peripherally restricted KOR agonists, we found that KOR-RGS6 anti-nociceptive signaling displays sex differences in a site-specific manner, as females but not males displayed enhanced anti-nociceptive and blunted nocifensive behaviors. Our findings suggest that RGS6 is a highly specific modulator of KOR-dependent anti-nociceptive signaling and plays an essential role in modulating nociceptive circuits, potentially aiding in the development of novel analgesic drugs and therapeutics.

pharmacology and toxicology↗

bioRxiv2025

Molecular basis for multidrug efflux by an anaerobic RND transporter

Bacteria can resist antibiotics and toxic substances within demanding ecological settings, such as low oxygen, extreme acid, and during nutrient starvation. MdtEF, a proton motive force-driven efflux pump from the resistance-nodulation-cell division (RND) superfamily, is upregulated in these conditions but its molecular mechanism is unknown. Here, we report cryo-electron microscopy structures of Escherichia coli multidrug transporter MdtF within native-lipid nanodiscs, including a single-point mutant with an altered multidrug phenotype and associated substrate-bound form. We reveal that drug binding domain and channel conformational plasticity likely governs promiscuous substrate specificity, analogous to its closely related, constitutively expressed counterpart, AcrB. Whereas we discover distinct transmembrane state transitions within MdtF, which create a more engaged proton relay network, altered drug transport allostery and an acid-responsive increase in efflux efficiency. Physiologically, this provides means of xenobiotic and metabolite disposal within remodelled cell membranes that presage encounters with acid stresses, as endured in the gastrointestinal tract.

biochemistry↗