β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors

Slosky, Lauren M.; Bai, Yushi; Tóth, K.; Ray, Caroline; Rochelle, Lauren K.; Badea, Alexandra; Chandrasekhar, Rahul; Pogorelov, Vladimir M.; Abraham, Dennis; Atluri, Namratha; Peddibhotla, Satyamaheshwar; Hedrick, Michael; Hershberger, Paul; Maloney, Patrick; Yuan, Hong; Li, Zibo; Wetsel, William C.; Pinkerton, Anthony B.; Barak, Lawrence S; Caron, Marc G.

doi:10.1016/j.cell.2020.04.053

Cited by 82 publications

(85 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Allosteric modulators have been shown to enhance the subtype selectivity of orthosteric ligands to closely related GPCRs [86,87]. Other studies detailed in these fine reviews have shown that allosteric modulators show bias to specific signaling pathways (G protein or β‐arrestin) and/or enhance the ligand bias of the orthosteric ligands [87,88]. Allosteric modulators bind to multiple structural regions of GPCRs highlighting the presence of druggable binding sites across GPCR structures.…”

Section: Discussionmentioning

confidence: 99%

Allosteric communication regulates ligand‐specific GPCR activity

Nivedha

Vaidehi

2021

The FEBS Journal

View full text Add to dashboard Cite

Accepted Article This article is protected by copyright. All rights reserved G protein coupled receptors (GPCRs) are membrane bound proteins that are ubiquitously expressed in many cell types and take part in mediating multiple signaling pathways. GPCRs are dynamic proteins and exist in an equilibrium between an ensemble of conformational states such as inactive and fully active states. This dynamic nature of GPCRs is one of the factors that confers their basal activity even in the absence of any ligand mediated activation. Ligands selectively bind and stabilize a subset of the conformations from the ensemble leading to a shift in the equilibrium towards the inactive or the active state depending on the nature of the ligand. This ligand-selective effect is achieved through allosteric communication between the ligand binding site and G protein or -arrestin coupling site. Similarly, the G protein coupling to the receptor exerts the allosteric effect on the ligand binding region leading to increased binding affinity for agonists and decreased affinity for antagonists or inverse agonists. In this review, we enumerate the current state of our understanding of the mechanism of allosteric communication in GPCRs with a specific focus on the critical role of computational methods in delineating the residues involved in allosteric communication. Analyzing allosteric communication mechanism using molecular dynamics simulations have revealed (i) a structurally conserved mechanism of allosteric communication that regulates the G protein coupling, (ii) a rational structure-based approach to designing selective ligands and (iii) an approach to designing allosteric GPCR mutants that are either ligand and G protein or -arrestin selective.

show abstract

Section: Discussionmentioning

confidence: 99%

Allosteric communication regulates ligand‐specific GPCR activity

Nivedha

Vaidehi

2021

The FEBS Journal

View full text Add to dashboard Cite

show abstract

“…Better understanding of the signaling pathways invoked by NtsR1 may also suggest clinical opportunities to safely potentiate NtsR1-mediated anorectic effects. For example, recently developed NtsR1 agonists biased for the β-arrestin-2 pathway do not produce cardiovascular liabilities ( 156 ) but reduce rodents’ intake of psychostimulants in a dopamine-dependent manner ( 156 , 158 ). While β-arrestin-2-biased agonists for NtsR1 have yet to be studied in regulating natural reward intake, these data reinvigorate the possibility of modulating beneficial Nts-NtsR1 signaling without endangering health.…”

Section: Translational Potential Of the Central Neurotensin System Fomentioning

confidence: 99%

The Role of Central Neurotensin in Regulating Feeding and Body Weight

Ramirez‐Virella

Leinninger

2021

Endocrinology

View full text Add to dashboard Cite

The small peptide Neurotensin (Nts) is implicated in myriad processes including analgesia, thermoregulation, reward, arousal, blood pressure and modulation of feeding and body weight. Alterations in Nts have recently been described in individuals with obesity or eating disorders, suggesting that disrupted Nts signaling may contribute to body weight disturbance. Curiously, Nts mediates seemingly opposing regulation of body weight via different tissues. Peripherally-acting Nts promotes fat absorption and weight gain, while central Nts signaling suppresses feeding and weight gain. Thus, because Nts is pleiotropic, a location-based approach must be used to understand its contributions to disordered body weight and whether the Nts system might be leveraged to improve metabolic health. Here we review the role of Nts signaling in the brain to understand the sites, receptors and mechanisms by which Nts can promote behaviors that modify body weight. New techniques permitting site-specific modulation of Nts and Nts receptor- expressing cells suggest that, even in the brain, not all Nts circuitry exerts the same function. Intriguingly, there may be dedicated brain regions and circuits via which Nts specifically suppresses feeding behavior and weight gain vs. other Nts-attributed physiology. Defining the central mechanisms by which Nts signaling modifies body weight may suggest strategies to correct disrupted energy balance, as needed to address overweight, obesity and eating disorders.

show abstract

“…Locomotor activity. The VersaMax activity monitor (Omnitech Electronics, Inc.) was used to assess locomotor activity, as previously described (59). Male and female mice with indwelling jugular catheters were acclimated to the open field for 30 min prior to administration (ip) of cocaine (20 mg/kg, 10 ml/kg) or remifentanil (0.1, 1.0 and 10 mg/kg, 10 ml/kg, sequentially).…”

mentioning

confidence: 99%

Establishment of Multi-stage Intravenous Self-administration Paradigms in Mice

Slosky

Pires

Bai

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

A major impediment to identifying the molecular substrates of addiction and developing effective therapeutics has been the lack of animal models that both recapitulate clinical disease presentation and are amenable to genetic manipulation. Intravenous self-administration is the “gold standard” for modeling cocaine and opioid addiction-associated behaviors in animals, but technical limitations have precluded its widespread use in mice, the mammalian species for which the most genetic tools are available. Here, we describe the establishment and demonstrate the utility of multi-stage cocaine and remifentanil paradigms that overcome classic challenges in murine intravenous self-administration. We evaluated self-administration acquisition, maintenance, extinction, and cue-induced reinstatement of drug seeking longitudinally in large cohorts of mice with indwelling catheters. In short daily sessions, mice without prior operant conditioning engaged in drug-associated lever responding that was fixed ratio- and dose-dependent, extinguished by the withholding of drugs, and reinstated by the reintroduction of paired cues. Multivariate statistics, to which this type of longitudinal data is well-suited, revealed that patterns of cocaine and remifentanil taking were similar while those of cocaine and remifentanil seeking were distinct. Individual performance in both drug paradigms was a function of two latent variables we termed incentive motivation and discriminative control. These latent variables identified drug class-specific self-administration phenotypes and were differentially predicted by a priori novelty- and drug-induced locomotor activity in the open field. Application of this behavioral and statistical analysis approach to genetically engineered mice will facilitate the identification of the cell types and neural circuits driving addictive behaviors and their underlying constructs.

show abstract

β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors

Cited by 82 publications

References 91 publications

Allosteric communication regulates ligand‐specific GPCR activity

Allosteric communication regulates ligand‐specific GPCR activity

The Role of Central Neurotensin in Regulating Feeding and Body Weight

Establishment of Multi-stage Intravenous Self-administration Paradigms in Mice

Contact Info

Product

Resources

About