Outputs (59)

Small Molecule Fluorescent Ligands for the Atypical Chemokine Receptor 3 (ACKR3) (2023)
Journal Article
Dekkers, S., Comez, D., Karsai, N., Arimont-Segura, M., Canals, M., Caspar, B., …Stocks, M. J. (2023). Small Molecule Fluorescent Ligands for the Atypical Chemokine Receptor 3 (ACKR3). ACS Medicinal Chemistry Letters, 15(1), 143–148. https://doi.org/10.1021/acsmedchemlett.3c00469

The atypical chemokine receptor 3 (ACKR3) is a receptor that induces cancer progression and metastasis in multiple cell types. Therefore, new chemical tools are required to study the role of ACKR3 in cancer and other diseases. In this study, fluoresc... Read More about Small Molecule Fluorescent Ligands for the Atypical Chemokine Receptor 3 (ACKR3).

Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity (2023)
Journal Article
Kirchhofer, S. B., Lim, V. J. Y., Ernst, S., Karsai, N., Julia, R. G., Canals, M., …Bünemann, M. (2023). Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity. eLife, 12, Article e91291. https://doi.org/10.7554/eLife.91291

The µ opioid receptor (MOR) is the key target for analgesia, but the application of opioids is accompanied by several issues. There is a wide range of opioid analgesics, differing in their chemical structure and their properties of receptor activatio... Read More about Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity.

Assessment of the potential of novel and classical opioids to induce respiratory depression in mice (2023)
Journal Article
Hill, R., Sanchez, J., Lemel, L., Antonijevic, M., Hosking, Y., Mistry, S. N., …Canals, M. (2023). Assessment of the potential of novel and classical opioids to induce respiratory depression in mice. British Journal of Pharmacology, 180(24), 3160-3174. https://doi.org/10.1111/bph.16199

Background and Purpose Opioid-induced respiratory depression limits the use of μ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respira... Read More about Assessment of the potential of novel and classical opioids to induce respiratory depression in mice.

Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D3 (D3R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics (2023)
Journal Article
Bonifazi, A., Saab, E., Sanchez, J., Nazarova, A. L., Zaidi, S. A., Jahan, K., …Newman, A. H. (2023). Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D3 (D3R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics. Journal of Medicinal Chemistry, 66(15), 10304–10341. https://doi.org/10.1021/acs.jmedchem.3c00417

A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D3 receptor (D3R) antagonist/partial agonists with optimized physicochemical properties was designed and synthesized. Combining in vitro cell-based on-target/off-target affinity... Read More about Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D3 (D3R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics.

OZITX, A pertussis toxin-like protein for occluding inhibitory G protein signalling including Gαz (2022)
Journal Article
Keen, A. C., Pedersen, M. H., Lemel, L., Scott, D. J., Canals, M., Littler, D. R., …Lane, J. R. (2022). OZITX, A pertussis toxin-like protein for occluding inhibitory G protein signalling including Gαz. Communications Biology, 5(1), Article 256. https://doi.org/10.1038/s42003-022-03191-5

Heterotrimeric G proteins are the main signalling effectors for G protein-coupled receptors. Understanding the distinct functions of different G proteins is key to understanding how their signalling modulates physiological responses. Pertussis toxin,... Read More about OZITX, A pertussis toxin-like protein for occluding inhibitory G protein signalling including Gαz.

The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine (2022)
Journal Article
Hill, R., Kruegel, A. C., Javitch, J. A., Lane, J. R., & Canals, M. (2022). The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine. British Journal of Pharmacology, 179(14), 3875-3885. https://doi.org/10.1111/bph.15832

Background and Purpose: Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the μ opioid receptor. CYP3A-dependent oxidation of mitragynine yields the metabolite 7-OH mitragynine, a more efficacious μ receptor agon... Read More about The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine.

Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gastrointestinal motility disorders (2021)
Journal Article
DiCello, J. J., Carbone, S. E., Saito, A., Pham, V., Szymaszkiewicz, A., Gondin, A. B., …Poole, D. P. (2022). Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gastrointestinal motility disorders. AJP - Gastrointestinal and Liver Physiology, 322(1), G66-G78. https://doi.org/10.1152/AJPGI.00297.2021

Allosteric modulators (AMs) are molecules that can fine-tune signaling by G protein-coupled receptors (GPCRs). Although they are a promising therapeutic approach for treating a range of disorders, allosteric modulation of GPCRs in the context of the... Read More about Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gastrointestinal motility disorders.

Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia (2021)
Journal Article
Lillywhite, A., Woodhams, S. G., Gonçalves, S. V., Watson, D. J. G., Li, L., Burston, J. J., …Chapman, V. (2021). Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia. PAIN Reports, 6(4), Article e956. https://doi.org/10.1097/PR9.0000000000000956

Introduction: Negative affect, including anxiety and depression, is prevalent in chronic pain states such as osteoarthritis (OA) and associated with greater use of opioid analgesics, potentially contributing to present and future opioid crises.... Read More about Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia.

Atypical opioid receptors: unconventional biology and therapeutic opportunities (2021)
Journal Article
Palmer, C. B., Meyrath, M., Canals, M., Kostenis, E., Chevigné, A., & Szpakowska, M. (2022). Atypical opioid receptors: unconventional biology and therapeutic opportunities. Pharmacology and Therapeutics, Article 108014. https://doi.org/10.1016/j.pharmthera.2021.108014

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating four opioid receptors, namely μ (mu, MOP), δ (delta, DOP), κ (kappa, KOP) and the nociceptin/orphanin FQ receptor (NOP). Interestingly, several o... Read More about Atypical opioid receptors: unconventional biology and therapeutic opportunities.

Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology (2021)
Journal Article
Hill, R., & Canals, M. (2022). Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology. Pharmacology and Therapeutics, 230, Article 107961. https://doi.org/10.1016/j.pharmthera.2021.107961

Morphine and other mu-opioid receptor (MOR) agonists remain the mainstay treatment of acute and prolonged pain states worldwide. The major limiting factor for continued use of these current opioids is the high incidence of side effects that result in... Read More about Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology.

Novel Dual-Target μ-Opioid Receptor and Dopamine D3 Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management (2021)
Journal Article
Bonifazi, A., Battiti, F. O., Sanchez, J., Zaidi, S. A., Bow, E., Makarova, M., …Newman, A. H. (2021). Novel Dual-Target μ-Opioid Receptor and Dopamine D3 Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management. Journal of Medicinal Chemistry, 64(11), 7778-7808. https://doi.org/10.1021/acs.jmedchem.1c00611

The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopami... Read More about Novel Dual-Target μ-Opioid Receptor and Dopamine D3 Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management.

Glycosylation Regulates N-Terminal Proteolysis and Activity of the Chemokine CCL14 (2021)
Journal Article
Wang, S., Foster, S. R., Sanchez, J., Corcilius, L., Larance, M., Canals, M., …Payne, R. J. (2021). Glycosylation Regulates N-Terminal Proteolysis and Activity of the Chemokine CCL14. ACS Chemical Biology, 16(6), 973-981. https://doi.org/10.1021/acschembio.1c00006

Chemokines are secreted proteins that regulate leukocyte migration during inflammatory responses by signaling through chemokine receptors. Full length CC chemokine ligand 14, CCL14(1–74), is a weak agonist for the chemokine receptor CCR1, but its act... Read More about Glycosylation Regulates N-Terminal Proteolysis and Activity of the Chemokine CCL14.

Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10 (2021)
Journal Article
Lim, H. D., Robert Lane, J., Canals, M., & Stone, M. J. (2021). Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10. International Journal of Molecular Sciences, 22(8), Article 4232. https://doi.org/10.3390/ijms22084232

Chemokines interact with chemokine receptors in a promiscuous network, such that each receptor can be activated by multiple chemokines. Moreover, different chemokines have been reported to preferentially activate different signalling pathways via the... Read More about Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10.

New phosphosite-specific antibodies to unravel the role of GRK phosphorylation in dopamine D2 receptor regulation and signaling (2021)
Journal Article
Mann, A., Keen, A. C., Mark, H., Dasgupta, P., Javitch, J. A., Canals, M., …Robert Lane, J. (2022). New phosphosite-specific antibodies to unravel the role of GRK phosphorylation in dopamine D2 receptor regulation and signaling. Scientific Reports, 11(1), Article 8288. https://doi.org/10.1038/s41598-021-87417-2

The dopamine D2 receptor (D2R) is the target of drugs used to treat the symptoms of Parkinson’s disease and schizophrenia. The D2R is regulated through its interaction with and phosphorylation by G protein receptor kinases (GRKs) and interaction with... Read More about New phosphosite-specific antibodies to unravel the role of GRK phosphorylation in dopamine D2 receptor regulation and signaling.

A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes (2021)
Journal Article
Mai, Q. N., Shenoy, P., Quach, T., Retamal, J. S., Gondin, A. B., Yeatman, H. R., …Veldhuis, N. A. (2021). A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes. Journal of Biological Chemistry, 296, Article 100345. https://doi.org/10.1016/J.JBC.2021.100345

G-protein-coupled receptors (GPCRs) are traditionally known for signaling at the plasma membrane, but they can also signal from endosomes after internalization to control important pathophysiological processes. In spinal neurons, sustained endosomal... Read More about A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes.

GRKs as Key Modulators of Opioid Receptor Function (2020)
Journal Article
Lemel, L., Lane, J. R., & Canals, M. (2020). GRKs as Key Modulators of Opioid Receptor Function. Cells, 9(11), Article 2400. https://doi.org/10.3390/cells9112400

Understanding the link between agonist-induced phosphorylation of the mu-opioid receptor (MOR) and the associated physiological effects is critical for the development of novel analgesic drugs and is particularly important for understanding the mecha... Read More about GRKs as Key Modulators of Opioid Receptor Function.

The life cycle of the Mu-Opioid Receptor (2020)
Journal Article
Cuitavi, J., Hipólito, L., & Canals, M. (2021). The life cycle of the Mu-Opioid Receptor. Trends in Biochemical Sciences, 46(4), 315-328. https://doi.org/10.1016/j.tibs.2020.10.002

Opioid receptors are undisputed targets for the treatment of pain. Unfortunately, targeting these receptors therapeutically poses significant challenges including addiction, dependence, tolerance and the appearance of side-effects such as respiratory... Read More about The life cycle of the Mu-Opioid Receptor.

Critical assessment of G protein-biased agonism at the µ opioid receptor (2020)
Journal Article
Gillis, A., Kliewer, A., Kelly, E., Henderson, G., Christie, M. J., Schulz, S., & Canals, M. (2020). Critical assessment of G protein-biased agonism at the µ opioid receptor. Trends in Pharmacological Sciences, 41(12), 947-959. https://doi.org/10.1016/j.tips.2020.09.009

G protein-biased agonists of the µ-opioid receptor have been proposed to be an improved class of opioid analgesics. Recent studies have been unable to reproduce the original experiments in the β-arrestin2 knockout mouse that led to this proposal, and... Read More about Critical assessment of G protein-biased agonism at the µ opioid receptor.

Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain (2020)
Journal Article
Jimenez-Vargas, N. N., Gong, J., Wisdom, M. J., Jensen, D. D., Latorre, R., Hegron, A., …Poole, D. P. (2020). Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain. Proceedings of the National Academy of Sciences, https://doi.org/10.1073/pnas.2000500117

Phosphoproteomic characterization of the signaling network resulting from activation of chemokine receptor CCR2 (2020)
Journal Article
Huang, C., Foster, S. R., Shah, A. D., Kleifeld, O., Canals, M., Schittenhelm, R. B., & Stone, M. J. (2020). Phosphoproteomic characterization of the signaling network resulting from activation of chemokine receptor CCR2. Journal of Biological Chemistry, 295, 6518-6531. https://doi.org/10.1074/jbc.ra119.012026

Leukocyte recruitment is a universal feature of tissue inflammation and regulated by the interactions of chemokines with their G protein-coupled receptors (GPCRs). Activation of CC chemokine receptor 2 (CCR2) by its cognate chemokine ligands, includi... Read More about Phosphoproteomic characterization of the signaling network resulting from activation of chemokine receptor CCR2.

Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists (2020)
Journal Article
Gillis, A., Gondin, A. B., Kliewer, A., Sanchez, J., Lim, H. D., Alamein, C., …Canals, M. (2020). Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists. Science Signaling, 13(625), Article eaaz3140. https://doi.org/10.1126/scisignal.aaz3140

Biased agonism at G protein–coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of... Read More about Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists.

Opioid pharmacology under the microscope (2020)
Journal Article
Jullé, D., Gondin, A. B., Canals, M., & Von Zastrow, M. E. (2020). Opioid pharmacology under the microscope. Molecular Pharmacology, Article mol.119.119321. https://doi.org/10.1124/mol.119.119321

A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor (2019)
Journal Article
Dekan, Z., Sianati, S., Yousuf, A., Sutcliffe, K. J., Gillis, A., Mallet, C., …Christie, M. J. (2019). A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor. Proceedings of the National Academy of Sciences, 116(44), 22353-22358. https://doi.org/10.1073/pnas.1908662116

An Australian estuarine isolate ofPenicilliumsp. MST-MF667 yielded3 tetrapeptides named the bilaids with an unusual alternating LDLDchirality. Given their resemblance to known short peptide opioidagonists, we elucidated that they were weak (Kilow mic... Read More about A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor.

Ligand-dependent spatiotemporal signaling profiles of the mu-opioid receptor are controlled by distinct protein-interaction networks (2019)
Journal Article
Civciristov, S., Huang, C., Liu, B., Marquez, E. A., Gondin, A. B., Schittenhelm, R. B., …Halls, M. L. (2019). Ligand-dependent spatiotemporal signaling profiles of the mu-opioid receptor are controlled by distinct protein-interaction networks. Journal of Biological Chemistry, 294(44), 16198-16213. https://doi.org/10.1074/jbc.ra119.008685

Ligand-dependent differences in the regulation and internalization of the mu-opioid receptor (MOR) have been linked to the severity of adverse effects that limit opiate use in pain management. MOR activation by morphine or [D-Ala2,N-MePhe4,Gly-ol]-en... Read More about Ligand-dependent spatiotemporal signaling profiles of the mu-opioid receptor are controlled by distinct protein-interaction networks.

Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1 (2019)
Journal Article
Sanchez, J., Lane, R., Canals, M., & Stone, M. J. (2019). Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1. International Journal of Molecular Sciences, 20(10), 1-15. https://doi.org/10.3390/ijms20102417

Leukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed i... Read More about Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1.

GRK mediates ?-opioid receptor plasma membrane reorganization (2019)
Journal Article
Gondin, A. B., Halls, M. L., Canals, M., & Briddon, S. J. (2019). GRK mediates ?-opioid receptor plasma membrane reorganization. Frontiers in Molecular Neuroscience, 12, https://doi.org/10.3389/fnmol.2019.00104

Differential regulation of the ?-opioid receptor (MOP) has been linked to the development of opioid tolerance and dependence which both limit the clinical use of opioid analgesics. At a cellular level, MOP regulation occurs via receptor phosphorylati... Read More about GRK mediates ?-opioid receptor plasma membrane reorganization.

G protein-coupled receptors are dynamic regulators of digestion and targets for digestive diseases (2019)
Journal Article
Canals, M., Poole, D. P., Veldhuis, N. A., Schmidt, B. L., & Bunnett, N. W. (2019). G protein-coupled receptors are dynamic regulators of digestion and targets for digestive diseases. Gastroenterology, 156(6), 1600-1616. https://doi.org/10.1053/j.gastro.2019.01.266

G protein-coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. Within the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neu... Read More about G protein-coupled receptors are dynamic regulators of digestion and targets for digestive diseases.

Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer (2019)
Journal Article
Blasco-Benito, S., Moreno, E., Seijo-Vila, M., Tundidor, I., Andradas, C., Caffarel, M. M., …Sánchez, C. (2019). Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer. Proceedings of the National Academy of Sciences, 116(9), 3863-3872. https://doi.org/10.1073/pnas.1815034116

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeut... Read More about Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer.

Evaluation and extension of the two-site, two-step model for binding and activation of the chemokine receptor CCR1 (2018)
Journal Article
Sanchez, J., e Huma, Z., Lane, J., Liu, X., Bridgford, J. L., Payne, R. J., …Stone, M. J. (2018). Evaluation and extension of the two-site, two-step model for binding and activation of the chemokine receptor CCR1. Journal of Biological Chemistry, 294(10), 3464-3475. https://doi.org/10.1074/jbc.ra118.006535

© 2019 Sanchez et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. Interactions between secreted immune proteins called chemokines and their cognate G protein– coupled receptors regulate the t... Read More about Evaluation and extension of the two-site, two-step model for binding and activation of the chemokine receptor CCR1.

Preassembled GPCR signaling complexes mediate distinct cellular responses to ultralow ligand concentrations (2018)
Journal Article
Civciristov, S., Ellisdon, A. M., Suderman, R., Pon, C. K., Evans, B. A., Kleifeld, O., …Halls, M. L. (2018). Preassembled GPCR signaling complexes mediate distinct cellular responses to ultralow ligand concentrations. Science Signaling, 11(551), Article eaan1188. https://doi.org/10.1126/scisignal.aan1188

G protein–coupled receptors (GPCRs) are the largest class of cell surface signaling proteins, participate in nearly all physiological processes, and are the targets of 30% of marketed drugs. Typically, nanomolar to micromolar concentrations of ligand... Read More about Preassembled GPCR signaling complexes mediate distinct cellular responses to ultralow ligand concentrations.

Hormones, neurotransmitters, growth factors, receptors, and signaling: Inflammation-associated changes in DOR expression and function in the mouse colon (2018)
Journal Article
Dicello, J., Saito, A., Rajasekhar, P., Eriksson, E., McQuade, R., Nowell, C., …Poole, D. (2018). Hormones, neurotransmitters, growth factors, receptors, and signaling: Inflammation-associated changes in DOR expression and function in the mouse colon. American Journal of Physiology, 315(4), G544-G559. https://doi.org/10.1152/ajpgi.00025.2018

Endoge-nous opioids activate opioid receptors (ORs) in the enteric nervous system to control intestinal motility and secretion. The μ-OR mediates the deleterious side effects of opioid analgesics, including constipation, respiratory depression, and a... Read More about Hormones, neurotransmitters, growth factors, receptors, and signaling: Inflammation-associated changes in DOR expression and function in the mouse colon.

Multisite phosphorylation is required for sustained interaction with GRKs and arrestins during rapid -opioid receptor desensitization (2018)
Journal Article
Miess, E., Gondin, A. B., Yousuf, A., Steinborn, R., Mösslein, N., Yang, Y., …Canals, M. (2018). Multisite phosphorylation is required for sustained interaction with GRKs and arrestins during rapid -opioid receptor desensitization. Science Signaling, 11(539), Article eaas9609. https://doi.org/10.1126/scisignal.aas9609

Copyright © 2018 The Authors. G protein receptor kinases (GRKs) and -arrestins are key regulators of -opioid receptor (MOR) signaling and trafficking. We have previously shown that high-efficacy opioids such as DAMGO stimulate a GRK2/3-mediated multi... Read More about Multisite phosphorylation is required for sustained interaction with GRKs and arrestins during rapid -opioid receptor desensitization.

Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome (2018)
Journal Article
Jimenez-Vargas, N. N., Pattison, L. A., Zhao, P., Lieu, T. M., Latorre, R., Jensen, D. D., …Bunnett, N. W. (2018). Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome. Proceedings of the National Academy of Sciences, 115(31), E7438-E7447. https://doi.org/10.1073/pnas.1721891115

© 2018 National Academy of Sciences. All rights reserved. Once activated at the surface of cells, G protein-coupled receptors (GPCRs) redistribute to endosomes, where they can continue to signal. Whether GPCRs in endosomes generate signals that contr... Read More about Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome.

Proteomic Identification of Interferon-Induced Proteins with Tetratricopeptide Repeats as Markers of M1 Macrophage Polarization (2018)
Journal Article
Huang, C., Lewis, C., Borg, N. A., Canals, M., Diep, H., Drummond, G. R., …Stone, M. J. (2018). Proteomic Identification of Interferon-Induced Proteins with Tetratricopeptide Repeats as Markers of M1 Macrophage Polarization. Journal of Proteome Research, 17(4), 1485-1499. https://doi.org/10.1021/acs.jproteome.7b00828

Macrophages, which accumulate in tissues during inflammation, may be polarized toward pro-inflammatory (M1) or tissue reparative (M2) phenotypes. The balance between these phenotypes can have a substantial influence on the outcome of inflammatory dis... Read More about Proteomic Identification of Interferon-Induced Proteins with Tetratricopeptide Repeats as Markers of M1 Macrophage Polarization.

Pharmacologic evidence for a putative conserved allosteric site on opioid receptors (2018)
Journal Article
Livingston, K., Stanczyk, M., Burford, N., Alt, A., Canals, M., & Traynor, J. (2018). Pharmacologic evidence for a putative conserved allosteric site on opioid receptors. Molecular Pharmacology, 93(2), 157-167. https://doi.org/10.1124/mol.117.109561

Allosteric modulators of G protein-coupled receptors, including opioid receptors, have been proposed as possible therapeutic agents with enhanced selectivity. BMS-986122 is a positive allosteric modulator (PAM) of the μ-opioid receptor (μ-OR). BMS-98... Read More about Pharmacologic evidence for a putative conserved allosteric site on opioid receptors.

Fluorescently Labeled Morphine Derivatives for Bioimaging Studies (2018)
Journal Article
Lam, R., Gondin, A. B., Canals, M., Kellam, B., Briddon, S. J., Graham, B., & Scammells, P. J. (2018). Fluorescently Labeled Morphine Derivatives for Bioimaging Studies. Journal of Medicinal Chemistry, 61(3), 1316-1329. https://doi.org/10.1021/acs.jmedchem.7b01811

Opioids, like morphine, are the mainstay analgesics for the treatment and control of pain. Despite this, they often exhibit severe side effects that limit dose; patients often become tolerant and dependent on these drugs, which remains a major health... Read More about Fluorescently Labeled Morphine Derivatives for Bioimaging Studies.

Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission (2017)
Journal Article
Yarwood, R., Imlach, W., Lieu, T., Veldhuis, N., Jensen, D., Herenbrink, C., …Bunnett, N. (2017). Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission. Proceedings of the National Academy of Sciences, 114(46), 12309-12314. https://doi.org/10.1073/pnas.1706656114

G protein-coupled receptors (GPCRs) are considered to function primarily at the plasma membrane, where they interact with extracellular ligands and couple to G proteins that transmit intracellular signals. Consequently, therapeutic drugs are designed... Read More about Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission.

Genetically Encoded FRET Biosensors to Illuminate Compartmentalised GPCR Signalling (2017)
Journal Article
Halls, M., & Canals, M. (2018). Genetically Encoded FRET Biosensors to Illuminate Compartmentalised GPCR Signalling. Trends in Pharmacological Sciences, 39(2), 148-157. https://doi.org/10.1016/j.tips.2017.09.005

Genetically encoded Förster resonance energy transfer (FRET) biosensors have been instrumental to our understanding of how intracellular signalling is organised and regulated within cells. In the last decade, the toolbox, dynamic range and applicatio... Read More about Genetically Encoded FRET Biosensors to Illuminate Compartmentalised GPCR Signalling.

Ticks from diverse genera encode chemokine-inhibitory evasin proteins (2017)
Journal Article
Hayward, J., Sanchez, J., Perry, A., Huang, C., Rodriguez Valle, M., Canals, M., …Stone, M. J. (2017). Ticks from diverse genera encode chemokine-inhibitory evasin proteins. Journal of Biological Chemistry, 292(38), 15670-15680. https://doi.org/10.1074/jbc.M117.807255

To prolong residence on their hosts, ticks secrete many salivary factors that target host defense molecules. In particular, the tick Rhipicephalus sanguineus has been shown to produce three salivary glycoproteins named “evasins,” which bind to host c... Read More about Ticks from diverse genera encode chemokine-inhibitory evasin proteins.

Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief (2017)
Journal Article
Porter, C. J., Lieu, T. M., Jensen, D. D., Lieu, T., Halls, M. L., Veldhuis, N. A., …Bunnett, N. W. (2017). Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief. Science Translational Medicine, 9(392), Article eaal3447. https://doi.org/10.1126/scitranslmed.aal3447

© 2017, American Association for the Advancement of Science. Typically considered to be cell surface sensors of extracellular signals, heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) control many pathophysiological processes... Read More about Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.

Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2 (2017)
Journal Article
Huma, Z. E., Sanchez, J., Lim, H. D., Bridgford, J. L., Huang, C., Parker, B. J., …Stone, M. J. (2017). Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2. Science Signaling, 10(480), Article eaai8529. https://doi.org/10.1126/scisignal.aai8529

Chemokines and their receptors collectively orchestrate the trafficking of leukocytes in normal immune function and inflammatory diseases. Different chemokines can induce distinct responses at the same receptor. In comparison to monocyte chemoattract... Read More about Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2.

Distribution and trafficking of the ?-opioid receptor in enteric neurons of the guinea pig (2016)
Journal Article
Lay, J., Carbone, S. E., DiCello, J. J., Bunnett, N. W., Canals, M., & Poole, D. P. (2016). Distribution and trafficking of the ?-opioid receptor in enteric neurons of the guinea pig. AJP - Gastrointestinal and Liver Physiology, 311(2), G252-G266. https://doi.org/10.1152/ajpgi.00184.2016

© 2016 the American Physiological Society. The μ-opioid receptor (MOR) is a major regulator of gastrointestinal motility and secretion and mediates opiate-induced bowel dysfunction. Although MOR is of physiological and therapeutic importance to gut f... Read More about Distribution and trafficking of the ?-opioid receptor in enteric neurons of the guinea pig.

Systematic analysis of factors influencing observations of biased agonism at the mu-opioid receptor (2016)
Journal Article
Thompson, G., Lane, J., Coudrat, T., Sexton, P., Christopoulos, A., & Canals, M. (2016). Systematic analysis of factors influencing observations of biased agonism at the mu-opioid receptor. Biochemical Pharmacology, 113, 70-87. https://doi.org/10.1016/j.bcp.2016.05.014

Biased agonism describes the ability of distinct G protein-coupled receptor (GPCR) ligands to stabilise distinct receptor conformations leading to the activation of different cell signalling pathways that can deliver different physiologic outcomes. T... Read More about Systematic analysis of factors influencing observations of biased agonism at the mu-opioid receptor.

Protein kinase D and G?? subunits mediate agonist-evoked translocation of protease-activated receptor-2 from the golgi apparatus to the plasma membrane (2016)
Journal Article
Jensen, D. D., Zhao, P., Jimenez-Vargas, N. N., Lieu, T. M., Gerges, M., Yeatman, H. R., …Bunnett, N. W. (2016). Protein kinase D and Gβγ subunits mediate agonist-evoked translocation of protease-activated receptor-2 from the golgi apparatus to the plasma membrane. Journal of Biological Chemistry, 291(21), 11285-11299. https://doi.org/10.1074/jbc.M115.710681

Agonist-evoked endocytosis of G protein-coupled receptors has been extensively studied. The mechanisms by which agonists stimulate mobilization and plasma membrane translocation of G protein-coupled receptors from intracellular stores are unexplored.... Read More about Protein kinase D and G?? subunits mediate agonist-evoked translocation of protease-activated receptor-2 from the golgi apparatus to the plasma membrane.

The role of kinetic context in apparent biased agonism at GPCRs (2016)
Journal Article
Javitch, J. A., Klein Herenbrink, C., Sykes, D. A., Donthamsetti, P., Canals, M., Coudrat, T., …Lane, J. R. (2016). The role of kinetic context in apparent biased agonism at GPCRs. Nature Communications, 7, Article 10842. https://doi.org/10.1038/ncomms10842

Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usu... Read More about The role of kinetic context in apparent biased agonism at GPCRs.

Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors (2016)
Journal Article
Shang, Y., Yeatman, H., Provasi, D., Alt, A., Christopoulos, A., Canals, M., & Filizola, M. (2016). Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors. ACS Chemical Biology, 11(5), 1220-1229. https://doi.org/10.1021/acschembio.5b00712

Available crystal structures of opioid receptors provide a high-resolution picture of ligand binding at the primary ("orthosteric") site, that is, the site targeted by endogenous ligands. Recently, positive allosteric modulators of opioid receptors h... Read More about Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors.

Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling (2016)
Journal Article
Halls, M., Yeatman, H., Nowell, C., Thompson, G., Gondin, A., Civciristov, S., …Canals, M. (2016). Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling. Science Signaling, 9(414), ra16-ra16. https://doi.org/10.1126/scisignal.aac9177

Differential regulation of the μ-opioid receptor (MOR), a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, contributes to the clinically limiting effects of opioid analgesics, such as morphine. We used biophysical appro... Read More about Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling.

Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the ?-Opioid Receptor (2015)
Journal Article
Schembri, L. S., Stoddart, L. A., Briddon, S. J., Kellam, B., Canals, M., Graham, B., & Scammells, P. J. (2015). Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the ?-Opioid Receptor. Journal of Medicinal Chemistry, 58(24), 9754-9767. https://doi.org/10.1021/acs.jmedchem.5b01664

Fluorescently labeled ligands are useful pharmacological research tools for studying receptor localization, trafficking, and signaling processes via fluorescence imaging. They are also employed in fluorescent binding assays. This study is centered on... Read More about Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the ?-Opioid Receptor.

The complex roles of ?-opioid receptor phosphorylation: A key determinant in receptor signaling and regulation (2015)
Journal Article
Canals, M. (2015). The complex roles of ?-opioid receptor phosphorylation: A key determinant in receptor signaling and regulation. Molecular Pharmacology, 88(4), 814-815. https://doi.org/10.1124/mol.115.100180

Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. This Commentary focuses on two articles in the October 2015 issue of Molecular Pharmacology that investigate the role of μ-opioid receptor phosphorylation in rec... Read More about The complex roles of ?-opioid receptor phosphorylation: A key determinant in receptor signaling and regulation.

Biased Agonism of Endogenous Opioid Peptides at the ?-Opioid Receptor (2015)
Journal Article
Thompson, G. L., Lane, J. R., Coudrat, T., Sexton, P. M., Christopoulos, A., & Canals, M. (2015). Biased Agonism of Endogenous Opioid Peptides at the ?-Opioid Receptor. Molecular Pharmacology, 88(2), 335-346. https://doi.org/10.1124/mol.115.098848

Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. Biased agonism is having a major impact on modern drug discovery, and describes the ability of distinct G protein-coupled receptor (GPCR) ligands to activate dif... Read More about Biased Agonism of Endogenous Opioid Peptides at the ?-Opioid Receptor.

Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the ?-opioid receptor (2015)
Journal Article
Burford, N. T., Livingston, K. E., Canals, M., Ryan, M. R., Budenholzer, L., Han, Y., …Alt, A. (2015). Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor. Journal of Medicinal Chemistry, 58(10), 4220-4229. https://doi.org/10.1021/acs.jmedchem.5b00007

© 2015 American Chemical Society. Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential fo... Read More about Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the ?-opioid receptor.

Detection and quantifi cation of intracellular signaling using fret-based biosensors and high content imaging (2015)
Book Chapter
Halls, M. L., Poole, D. P., Ellisdon, A. M., Nowell, C. J., & Canals, M. (2015). Detection and quantifi cation of intracellular signaling using fret-based biosensors and high content imaging. In G Protein-Coupled Receptors in Drug Discovery, (131-161). (2nd). Humana Press. https://doi.org/10.1007/978-1-4939-2914-6_10

© Springer Science+Business Media New York 2015. Förster resonance energy transfer (FRET) biosensors represent invaluable tools to detect the spatiotemporal context of second messenger production and intracellular signaling that cannot be attained us... Read More about Detection and quantifi cation of intracellular signaling using fret-based biosensors and high content imaging.

Detection and quantification of allosteric modulation of endogenous M4 muscarinic acetylcholine receptor using impedance-based label-free technology in a neuronal cell line (2014)
Journal Article
Chen, A. N., Chen, A., Malone, D. T., Pabreja, K., Sexton, P. M., Christopoulos, A., & Canals, M. (2014). Detection and quantification of allosteric modulation of endogenous M4 muscarinic acetylcholine receptor using impedance-based label-free technology in a neuronal cell line. Journal of Biomolecular Screening, 20(5), 646-654. https://doi.org/10.1177/1087057114563025

© 2014 Society for Laboratory Automation and Screening. Allosteric modulators of G protein-coupled receptors have the potential to achieve greater receptor subtype selectivity compared with ligands targeting the orthosteric site of this receptor fami... Read More about Detection and quantification of allosteric modulation of endogenous M4 muscarinic acetylcholine receptor using impedance-based label-free technology in a neuronal cell line.

Structural basis of receptor sulfotyrosine recognition by a cc chemokine: The n-terminal region of CCR3 bound to CCL11/eotaxin-1 (2014)
Journal Article
Millard, C. J., Ludeman, J. P., Canals, M., Bridgford, J. L., Hinds, M. G., Clayton, D. J., …Stone, M. J. (2014). Structural basis of receptor sulfotyrosine recognition by a cc chemokine: The n-terminal region of CCR3 bound to CCL11/eotaxin-1. Structure, 22(11), 1571-1581. https://doi.org/10.1016/j.str.2014.08.023

© 2014 Elsevier Ltd. Trafficking of leukocytes in immune surveillance and inflammatory responses is activated by chemokines engaging their receptors. Sulfation of tyrosine residues in peptides derived from the eosinophil chemokine receptor CCR3 drama... Read More about Structural basis of receptor sulfotyrosine recognition by a cc chemokine: The n-terminal region of CCR3 bound to CCL11/eotaxin-1.

Mechanistic Insights into Allosteric Structure-Function Relationships at the M1 Muscarinic Acetylcholine Receptor (2014)
Journal Article
Abdul-Ridha, A., Lane, J. R., Mistry, S. N., Lopez, L., Sexton, P. M., Scammells, P. J., …Canals, M. (2014). Mechanistic Insights into Allosteric Structure-Function Relationships at the M1 Muscarinic Acetylcholine Receptor. Journal of Biological Chemistry, 289(48), 33701-33711. https://doi.org/10.1074/jbc.m114.604967

Benzylquinolone carboxylic acid (BQCA) is the first highly selective positive allosteric modulator (PAM) for the M1 muscarinic acetylcholine receptor (mAChR), but it possesses low affinity for the allosteric site on the receptor. More recent drug dis... Read More about Mechanistic Insights into Allosteric Structure-Function Relationships at the M1 Muscarinic Acetylcholine Receptor.

Endothelin-converting enzyme 1 and ?-arrestins exert spatiotemporal control of substance P-induced inflammatory signals (2014)
Journal Article
Jensen, D. D., Halls, M. L., Murphy, J. E., Canals, M., Cattaruzza, F., Poole, D. P., …Bunnett, N. W. (2014). Endothelin-converting enzyme 1 and β-arrestins exert spatiotemporal control of substance P-induced inflammatory signals. Journal of Biological Chemistry, 289(29), 20283-20294. https://doi.org/10.1074/jbc.M114.578179

Although the intracellular trafficking of G protein-coupled receptors controls specific signaling events, it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation. By using bio... Read More about Endothelin-converting enzyme 1 and ?-arrestins exert spatiotemporal control of substance P-induced inflammatory signals.

Novel GPCR paradigms at the ?-opioid receptor (2014)
Journal Article
Thompson, G. L., Kelly, E., Christopoulos, A., & Canals, M. (2015). Novel GPCR paradigms at the ?-opioid receptor. British Journal of Pharmacology, 172(2), 287-296. https://doi.org/10.1111/bph.12600

© 2014 The British Pharmacological Society. Opioids, such as morphine, are the most clinically useful class of analgesic drugs for the treatment of acute and chronic pain. However, the use of opioids is greatly limited by the development of severe ad... Read More about Novel GPCR paradigms at the ?-opioid receptor.

Allosteric modulation of M1 muscarinic acetylcholine receptor internalization and subcellular trafficking (2014)
Journal Article
Yeatman, H. R., Lane, J. R., Choy, K. H. C., Lambert, N. A., Sexton, P. M., Christopoulos, A., & Canals, M. (2014). Allosteric modulation of M1 muscarinic acetylcholine receptor internalization and subcellular trafficking. Journal of Biological Chemistry, 289(22), 15856-15866. https://doi.org/10.1074/jbc.M113.536672

Background: The effects of allosteric modulators on G protein-coupled receptor trafficking are largely unknown. Results: The allosteric ligand BQCA modulates M1 mAChR arrestin recruitment and receptor trafficking. Conclusion: M1 mAChR trafficking is... Read More about Allosteric modulation of M1 muscarinic acetylcholine receptor internalization and subcellular trafficking.

Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor (2014)
Journal Article
Abdul-Ridha, A., López, L., Keov, P., Thal, D. M., Mistry, S. N., Sexton, P. M., …Christopoulos, A. (2014). Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor. Journal of Biological Chemistry, 289(9), 6067-6079. https://doi.org/10.1074/jbc.M113.539080

Benzylquinolone carboxylic acid (BQCA) is an unprecedented example of a selective positive allosteric modulator of acetylcholine at the M1 muscarinic acetylcholine receptor (mAChR). To probe the structural basis underlying its selectivity, we utilize... Read More about Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor.