Biology subjects

Ulven, T.

Publications and source records attributed to Ulven, T..

7 recordsLinked to original sources

bioRxiv2026

Development of Potent G Protein Pathway-Biased GPR183 Agonists

GPR183 is an oxysterol-sensing GPCR predominantly expressed in lymphoid organs and tissues. Activation of the receptor by oxysterol 7,25-OHC leads to Gi protein-mediated signaling as well as {beta}-arrestin2 recruitment. GPR183/oxysterol signaling modulates localization of lymphoid cells, consequently the receptor is associated with several inflammation-associated diseases and is an interesting potential drug target. Previously, we reported the discovery of moderately potent G protein-biased partial agonists for GPR183 from a virtual screening based on the scaffold of the antagonist NIBR189. Herein, we present the detailed structure-activity investigations and optimizations, which led to the identification of full agonists for GPR183 with complete bias for Gi protein signaling and low nanomolar potency, including 63 (TUG-2604) with potency and efficacy similar to 7,25-OHC. Notably, 63 was unable to induce migration of human dendritic cells but inhibited migration induced by 7,25-OHC. This compound will be valuable for further explorations of the signaling-specific function and drug target potential of GPR183.

pharmacology and toxicology↗

bioRxiv2024

The SH Protein of Mumps Virus is a Druggable Pentameric Viroporin

Viral infections are on the rise and drugs targeting viral proteins are needed. Viroporins constitute a growing group of virus-encoded transmembrane oligomeric proteins that allow passage of small molecules across the membrane. Despite sparsity in viroporin structures, recent work has revealed diversity in both the number of transmembrane helices and oligomeric states. Here we provide evidence that the small hydrophobic protein (SH) from mumps virus is a pentameric viroporin. From extensive biophysical data, a HADDOCK model of full-length SH shows its intracellular C-terminal region to form an extended structure crucial to stabilization of the pentamer. Heterologous expression of wild type SH and variants in Xenopus laevis oocytes reveals the viroporin as a chloride channel, facilitated by conserved hydroxyl-carrying residues lining the pore. The channel function of SH is inhibited by the small-molecule BIT225, highlighting the potential for antiviral targeting through SH.

biophysics↗

bioRxiv2024

Multi-Coloured Sequential Resonance Energy Transfer for Simultaneous Ligand Binding at G Protein-Coupled Receptors

G protein coupled receptors (GPCRs) are the largest family of signalling proteins and highly successful drug targets. Most GPCR drugs interact with a binding pocket for the natural ligand, typically near the extracellular region of the transmembrane domains. Advancements in structural biology have identified additional allosteric binding sites in other parts of these receptors. Allosteric sites provide theoretical advantages, including the ability to modulate natural ligand function, and there is a need for better ways to study how ligands interact with these binding sites. We have developed an approach to study multiple ligands binding to the same receptor at the same time based on sequential resonance energy transfer between two fluorescent ligands bound to a GPCR. We use this approach to identify novel ligand pharmacology and understand binding kinetics to the FFA1 free fatty acid receptor, a clinically relevant receptor. This novel method will aid development of new GPCR drugs.

pharmacology and toxicology↗

bioRxiv2024

Nutrient Sensing Receptor GPRC6A Regulates mTORC1 Signaling and Tau Biology

Tauopathies, including Alzheimers disease (AD), comprise microtubule-associated protein tau aggregates that cause neuronal cell death and clinical cognitive decline. Reducing overall tau abundance remains a central strategy for therapeutics; however, no disease-modifying treatment exists to date. One principal pathway for balancing cellular proteostasis includes the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Recently, arginine emerged as one of the primary amino acids to activate mTORC1 through several intracellular arginine sensors and an extracellular arginine receptor, namely the G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A). Human AD brains were previously reported with elevated mTORC1 signaling; however, it is unclear whether arginine sensing and signaling to mTORC1 plays a role in tauopathies. Herein, we examined arginine sensing associated with mTORC1 signaling in the human AD and animal models of tauopathy. We found that human AD brains maintained elevated levels of arginine sensors with potential uncoupling of arginine sensing pathways. Furthermore, we observed increased GPRC6A and arginine in the brain, accompanied by increased mTORC1 signaling and decreased autophagy in a mouse model of tauopathy (Tau PS19). We also discovered that both supplementing arginine and overexpressing GPRC6A in cell culture models could independently activate mTORC1 and promote tau accumulation. In addition, we found that suppressing GPRC6A signaling by either genetic reduction or pharmacological antagonism reduced tau accumulation, phosphorylation, and oligomerization. Overall, these findings uncover the crucial role of arginine sensing pathways in deregulating mTORC1 signaling in tauopathies and identify GPRC6A as a promising target for future therapeutics in tauopathies and other proteinopathies. Significance StatementTauopathies, including Alzheimers disease (AD), accumulate pathogenic tau protein inclusions that potentially contribute to the hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling and eventually cause neuronal cell death. Here, we presented novel findings that AD and animal models of tauopathy maintained increased expression of arginine sensors and uncoupling of arginine sensing associated with mTORC1 signaling. We investigated the role of a putative extracellular arginine and basic L-amino acid sensing G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A) in activating mTORC1 and accelerating pathogenic tau phenotypes in several cell models. Additionally, we showed that genetic repression or antagonism of GPRC6A signaling provides a novel therapeutic target for tauopathies and other proteinopathies.

neuroscience↗

bioRxiv2020

The two formyl peptide receptors differently regulate GPR84-mediated neutrophil NADPH-oxidase activity

Neutrophils express many G protein-coupled receptors (GPCRs) including the two formyl peptide receptors (FPR1 and FPR2) and the medium chain fatty acid receptor GPR84. The FPRs are known to define a hierarchy among neutrophil GPCRs, i.e., the GPCR-mediated response can be either suppressed or amplified by signals generated by FPRs. In this study, we investigated the position of GPR84 in the FPR-defined hierarchy regarding the activation of neutrophil NADPH-oxidase, an enzyme system designed to generate reactive oxygen species (ROS). When naive neutrophils are activated by GPR84 agonists a modest ROS release was induced. However, vast amounts of ROS production was induced by these GPR84 agonists in FPR2-desensitized neutrophils, and the response is inhibited not only by a GPR84 antagonist but also by an FPR2 specific antagonist. This suggests that the amplified GPR84 agonist response is achieved through a reactivation of the desensitized FPR2. In addition, the GPR84-mediated FPR2 reactivation was independent of {beta}-arrestin recruitment and sensitive to a protein phosphatase inhibitor. In contrast, the modest ROS production induced by GPR84 agonists was primarily suppressed in FPR1-desensitized neutrophils through hierarchical desensitization of GPR84 by FPR1 generated signals. In summary, our data show that FPRs control the NADPH-oxidase activity mediated through GPR84 in human neutrophils. While an amplified ROS generation is achieved by GPR84 agonists through reactivation of desensitized FPR2, FPR1 heterologously desensitizes GPR84 and by that suppresses the release of ROS induced by GPR84 agonists.

immunology↗

bioRxiv2020

Pathophysiological regulation of lung function by the free fatty acid receptor FFA4

Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with a significant number of patients being inadequately controlled by current frontline treatments means that there is a need to define novel therapeutic targets for these conditions1. Here we investigate a member of the G protein-coupled receptor (GPCR) family, FFA4, which responds to free circulating fatty acids, including dietary omega-3 fatty acids found in fish oils2–4. Although usually associated with metabolic responses linked with food intake, we show that FFA4 is expressed in the lung where it is coupled to Gq/11-signalling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated, at least in part, by the release of the prostaglandin PGE2 that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. Importantly, in acute and chronic ozone models of pollution-mediated inflammation, and in house-dust mite and cigarette smoke-induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, whilst this response was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was very similar to that observed in mice and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation. Hence, our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy that might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pharmacology and toxicology↗

bioRxiv2020

Chemogenetic analysis of how receptors for short chain fatty acids regulate the gut-brain axis

The gut-brain axis allows bi-directional communication between the enteric and central nervous systems. Short chain fatty acids (SCFAs) generated by the gut microbiota are important regulators of this interface. However, defining mechanisms by which SCFAs do so has been challenging because, amongst various roles, they co-activate both of a pair of closely related and poorly characterized G protein-coupled receptors, FFA2 and FFA3. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) can provide an important approach in defining receptor-specific functions. By screening a library of carboxylate-containing small molecules we identified 4-methoxy-3-methyl-benzoic acid (MOMBA) as a specific agonist of a DREADD variant of FFA2 which is not activated by SCFAs. Using mice engineered to replace FFA2 with this FFA2-DREADD, whilst retaining FFA3 expression, combinations of MOMBA and the now FFA3 receptor selective SCFAs defined key, but distinct, roles of FFA2 and FFA3 in each of gut transit time, secretion of entero-endocrine hormones, and communication from the gut to each of autonomic and somatic sensory ganglion cells and the spinal cord. These studies map mechanisms and signalling pathways by which each of FFA2 and FFA3 act to link the gut and the brain and provide both animal models and novel tool compounds to further explore this interface.

pharmacology and toxicology↗