About

Professor Lauren Slosky is associated with the Medical Discovery Team on Addiction at the University of Minnesota Medical School. The team is dedicated to making rapid advancements in understanding brain mechanisms of addiction and relapse, and translating these discoveries into new effective therapies to prevent and treat addiction. The overarching goal of the team is to link brain-based discoveries to new therapeutic approaches, aiming to improve patient outcomes and contribute to the field of addiction research and treatment.

Research topics

• Biochemistry
• Biology
• Pharmacology
• Neuroscience
• Cell biology
• Biophysics
• Chemistry
• Computational biology
• Psychology
• Bioinformatics

Selected publications

• Rare variant in intracellular loop-2 alters the spatial distribution and transducer coupling selectivity of the ghrelin receptor

  Molecular Pharmacology · 2026-03-13

  articleOpen access

  coupling efficacy; (3) expands GPCR kinase (GRK) subclass utilization from GRK2/3-dependent to an additional, partial reliance on GRK5/6; and (4) promotes βarr1/2 recruitment independent of G protein-mediated second messenger kinase activation. The evolutionary conservation of the ProH motif suggests that cognate, ICL2-destabilizing variants likely confer comparable disruptions in GPCR structure/function beyond established effects on G protein coupling. Collectively, these results establish a naturalistic model to study ICL2-dependent GPCR regulation and illuminate the ProH motif as a promising drug target for biased allosteric modulators. SIGNIFICANCE STATEMENT: G protein-coupled receptors are the most common pharmaceutical target in medicine. This study exploited a rare variant in intracellular loop-2 of the ghrelin receptor to characterize a conserved, allosteric "hotspot" controlling G protein-coupled receptor expression, trafficking, and signaling. These findings highlight intracellular loop-2 as a promising target for biased allosteric modulator drug design.

  PublisherDOI

• Biased signaling at NTSR1 differentially regulates inhibitory synaptic transmission in the extended amygdala and suppresses motivated feeding in mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-05

  articleOpen access

  Abstract Maladaptive consummatory behaviors can arise from dysregulated circuits, like the extended amygdala that governs motivation and feeding. Neurotensin (NTS) is expressed throughout the central, peripheral, and enteric nervous systems with well-established roles in energy balance and feeding. SBI-553, a β-arrestin-biased allosteric modulator of NTSR1, recruits β-arrestin while attenuating G q -mediated signaling. We used SBI-553 to examine NTS modulation of extended amygdala GABAergic signaling, and probed its effects on food consumption in mice. Ex vivo , we found that NTS and SBI-553 differentially modulates GABAergic neurotransmission across extended amygdala subregions. In vivo , SBI-553 reduces palatable food consumption in both fed and food-deprived mice, with greater reductions under fasted conditions. SBI-553 alters activation across CeA subregions in a sex- and feeding-state-dependent manner: SBI-553 increases cFos immunofluorescence in the CeA L and CeA C , but not the CeA M . This work supports neurotensinergic modulation as a compelling target for further investigation into the neural substrates of consummatory behaviors. Highlights NTS enhances GABAergic transmission in the CeA L and the ovBNST SBI-553 blocks NTS-induced modulation in the CeA L but not in the ovBNST SBI-553 attenuates feeding of a palatable high-carbohydrate food The effect of SBI-553 on feeding is driven by energy deficit/motivation to feed Graphical Abstract

  PublisherDOI

• Designing allosteric modulators to change GPCR G protein subtype selectivity

  Nature · 2025-10-22 · 9 citations

  articleOpen accessSenior author

  G-protein-coupled receptors (GPCRs) convert extracellular signals into intracellular responses by signalling through 16 subtypes of Gα proteins and two β-arrestin proteins. Biased compounds—molecules that preferentially activate a subset of these proteins—engage therapy-relevant pathways more selectively1 and promise to be safer, more effective medications than compounds that uniformly activate all pathways2. However, the determinants of bias are poorly understood, and we lack rationally designed molecules that select for specific G proteins. Here, using the prototypical class A GPCR neurotensin receptor 1 (NTSR1), we show that small molecules that bind to the intracellular GPCR–transducer interface change G protein coupling by subtype-specific and predictable mechanisms, enabling structure-guided drug design. We find that the intracellular, core-binding compound SBI-553 switches the G protein preference of NTSR1 through direct intermolecular interactions3–5, promoting or preventing association with specific G protein subtypes. Modifications to the SBI-553 scaffold produce allosteric modulators with distinct G protein selectivity profiles. Selectivity profiles are probe independent, conserved across species and translate to differences in activity in vivo. Our studies show that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the receptor–transducer interface. Moreover, given that this pocket is broadly conserved, our findings could provide a strategy for pathway-selective drug discovery that is applicable to the diverse GPCR superfamily. Studies of the G-protein-coupled receptor NTSR1 show that the G protein selectivity of this receptor can be modified by small molecules, enabling the design of drugs that work by switching receptor subtype preference.

  PublisherOA PDFDOI

• Hidden Bias: GPCR Polymorphisms and the Genomic Landscape of β-Arrestin Signaling

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-06

  preprintOpen access

  Abstract Clinically, no human diseases are currently diagnosed as being directly driven by β- arrestins. Nonetheless, there is growing interest in developing β-arrestin–biased drugs, due to the key regulatory role of β-arrestins in modulating the cellular signaling of most G protein–coupled receptors (GPCRs). In cell-based studies of rhodopsin-family GPCRs, mutations in a conserved proline–hydrophobic (ProH) motif within the second intracellular loop (ICL2) have been shown to alter β-arrestin signaling bias. The clinical relevance of such mutations in humans is unknown. However, if naturally occurring single nucleotide polymorphisms (SNPs) affecting this ProH motif exist across the GPCR family, then cross-referencing these genetic variants with large-scale population sequencing and epidemiologic data could reveal potential roles for β-arrestin signaling in human health. In this report, we identify SNPs in human GPCRs that correspond to ProH substitutions, and we show that, in the neurotensin receptor NTSR1, these variants can indeed shift signaling bias. We also estimate a lower-bound population frequency for such SNPs, suggesting that although rare for any given receptor, their cumulative prevalence across the GPCR superfamily may be large enough to impact phenotypic variation. Together with emerging data from biased ligands, our findings support the idea that genetic variations in β-arrestin signaling could represent a meaningful source of therapeutic relevance. Significance statement Mutations altering G protein-coupled receptor (GPCR) signaling can affect health. We have identified a specific amino acid determinant in intracellular loop (ICL2) of human rhodopsin family GPCRs that influences β-arrestin signaling. Although the medical consequences of this determinant remain unclear, we show that single nucleotide polymorphisms (SNPs) affecting the determinant routinely occur. By studying neurotensin receptor NTSR1, we confirm that the SNP alters β-arrestin signaling bias. While individually rare per receptor, these SNPs may collectively contribute to β-arrestin-related phenotypic changes in the human population. Our findings, combined with research on biased drugs, support the idea that β-arrestin signaling might serve as a useful therapeutic target, opening new possibilities for precision medicine.

  PublisherOA PDFDOI

• Arrestin-biased allosteric modulator of neurotensin receptor 1 alleviates acute and chronic pain

  Cell · 2025-05-19 · 26 citations

  articleOpen access
  PublisherOA PDFDOI

• Editorial: GPCRs: signal transduction

  Frontiers in Molecular Biosciences · 2024-04-10 · 2 citations

  editorialOpen accessSenior authorCorresponding

  The manuscripts in this collection explore GPCR signaling (Birch et al., Matt et al., Qiu et al., Pogorelov et al.), adaptor proteins that shape this signaling (Ye et al.), and regulatory proteins that integrate G protein and non-G protein-linked signals (Tian et al. and Yang et al.). These reports set the stage for an understanding of GPCR function in both health and disease. For example, Birch et al. investigated how activated protein C (APC) interacts with the GPCR protease-activated receptor-1 (PAR1) to induce cytoprotective responses in endothelial cells. PAR1 beta-arrestin2 activation is a promising target for the treatment of vascular diseases, but the mechanism by which this complex elicits its cytoprotective responses is unknown. Birch et al. report that APC alters the phosphorylation of TNF-α signal pathway components, reducing TNF-α-induced expression of the inflammation-related marker VCAM-1. Unexpectedly, Birch et al. also find that different APC/PAR1 cytoprotective responses are mediated by discrete β-arrestin-2-mediated signaling pathways, driven by the presence of coreceptors and GPCR kinases (GRKs).Behavioral consequences of functional selectivity or biased GPCR signaling are highlighted by Pogorelov et al. Pogorelov et al. examined the behavioral effect of serotonin 2A receptor (5-HT2AR) activation by two different ligands: lisuride (marketed as Dopergin for Parkinson's disease) and LSD (lysergic acid diethylamide). Although lisuride and LSD are both high-affinity 5-HT2AR partial agonists and share structural similarities, only LSD induces hallucinogenic effects in healthy subjects at routine doses. At the 5-HT2AR, lisuride is G protein-biased, while LSD is beta-arrestin2-biased. Pogorelove et al. report that, in mouse models, lisuride exerted anti-depressant drug-like responses without hallucinogenic-like activities, including in beta-arrestin1 and beta-arrestin2 KO mice. These data suggest that beta-arrestin1 and beta-arrestin2 play minor roles in many of lisuride's behavioral effects and that lisuride's beneficial actions may be a result of G protein-biased 5-HT2AR signaling.The role of GPCR regulatory proteins in cancer was the subject of several reports in this Research Topic. Ye et al. examined the expression of beta-arrestin1 (ARRB1), a key GPCR adaptor, in 33 cancer types. Ye et al. correlated beta-arrestin1 expression levels with cancer prognosis, the tumor microenvironment, and response to immunotherapy. Yet et al. found that ARRB1 expression was lower in almost 50% of tumor tissues assessed than non-cancerous tissues. This suggests that ARRB1 may have prognostic value in cancer, especially for predicting response to immune-based cancer therapeutics. Another study by Yang et al.systematically investigated the impact of GPCR-regulating RGS proteins in gastric cancer. They found that RGS22, RGS3, RGS4, and RGS5 commonly exhibit copy number amplifications in gastric cancer. Elevated expression of RGS1, RGS2, and RGS3 was associated with poor disease prognosis, with RGS5 linked to abnormal vascular formation. Specifically, they highlighted the role of RGS4 in controlling fibroblast infiltration and epithelialmesenchymal transition. The pathophysiological relevance of RGS16 in cancer, inflammation, and metabolic disorders is reviewed by Tian et al. The authors synthesized work on the contribution of RGS16 to cancer-related immune, inflammatory, and metabolic processes. RGS16-regulated signaling pathways in these disease states include MAPKs (mitogenactivated protein kinases), PI3Ks/PKB (phosphoinositide 3-kinase/protein kinase B), ROHA (Ras homolog family member A), and SDF-1/CXCR4 (stromal cell-derived factor 1/C-X-C motif chemokine receptor four).Moving from assessments of GPCR adapters and regulatory proteins back to the receptors themselves, Matt et al. investigated the signaling diversity of β-adrenergic receptors (β-ARs) expressed in the central nervous system. Matt et al. used ligand-induced Emax (maximal response level) and EC50 (half maximal effective concentration) in conjunction with reference agonist values to create system-independent "fingerprints" for β-AR subtypes. These fingerprints were then used to assess receptor subtype expression across human brain cell systems. β2-AR functional expression was identified across several human brain cell types. The final report in this Research Topic highlights the power of GPCR screening for therapeutic discovery. With the goal of identifying new targets for the improvement of cardiovascular health, Qiu et al. undertook a screen to identify GPCRs controlling expression of a zinc-finger transcription factor that promotes endothelium health: KFL2 (Krüppel-like Factor 2). This screen identified several novel anti-atherosclerotic GPCR loci, including GPR116, SSTR3, GPR101, and LGR4. Qiu et al. go on to describe their drug discovery efforts surrounding LGR4, highlighting its potential as a therapeutic target for improving endothelial function in cardiovascular disease.To conclude, research on GPCR signal transduction reveals new strategies for engaging established receptor targets to bring about more directed pharmacological action. Additionally, this research is continuing to identify new GPCR regulatory proteins with both therapeutic and prognostic potential. Understanding the diversity of possible GPCR signaling outcomes, driven via ligand bias and/or system bias, will facilitate the development of pathway-selective GPCRtargeted therapeutics. The ability to monitor and quantify GPCR signaling via multiple pathways and across levels of evaluation, from regionally restricted second messengers/effectors to cellular, physiological, and behavioral responses, will be critical to this effort. We thank the authors for contributing their outstanding work to this Research Topic.

  PublisherOA PDFDOI

• Biased allosteric modulator of neurotensin receptor 1 reduces ethanol drinking and responses to ethanol administration in rodents

  Addiction Neuroscience · 2024-11-02 · 3 citations

  articleOpen access

  Alcohol use disorders (AUDs) impose an enormous societal and financial burden, and world-wide, alcohol misuse is the 7th leading cause of premature death [1]. Despite this, there are currently only 3 FDA approved pharmacological approaches for the treatment of AUDs in the United States. The neurotensin (Nts) system has long been implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, that biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psychostimulant use. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, physiological sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances.

  PublisherDOI

• Design of allosteric modulators that change GPCR G protein subtype selectivity

  Research Square · 2024-12-11

  preprintOpen access1st authorCorresponding
  PublisherDOI

• β-arrestin-biased Allosteric Modulator of Neurotensin Receptor 1 Reduces Ethanol Drinking and Responses to Ethanol Administration in Rodents

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-04-13 · 5 citations

  preprintOpen access

  . Despite this, there are currently only 3 FDA approved pharmacological treatments for the treatment of AUDs in the United States. The neurotensin (Nts) system has long been implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, that biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psychostimulant misuse. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces binge-like ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances.

  PublisherOA PDFDOI

• Biased Allosteric Modulator of Neurotensin Receptor 1 Reduces Ethanol Drinking and Responses to Ethanol Administration in Rodents

  UNC Libraries · 2024-11-15

  articleOpen access
  PublisherDOI

Recent grants

• Leveraging Functional Selectivity in the Neurotensin Receptor 1-Mediated Treatment of Addiction

  NIH · $747k · 2019–2024

• Biased Agonism at Neurotensin Receptor 1 for the Treatment of Methamphetamine Addiction

  NIH · $124k · 2017–2020

• Leveraging Functional Selectivity in the Neurotensin Receptor 1-Mediated Treatment of Addiction

  NIH · $361k · 2019–2021

Frequent coauthors

• Marc G. Caron

  Duke University Hospital

  39 shared

• Lawrence S Barak

  Duke University

  38 shared

• Krisztián Tóth

  35 shared

• Caroline Ray

  Duke University

  21 shared

• William C. Wetsel

  Duke University

  15 shared

• Nicholas Clark

  Duke University

  14 shared

• Anthony B. Pinkerton

  Boundless Bio (United States)

  13 shared

• Karim Nagi

  Duke University

  12 shared