Ligand-directed signalling within the opioid receptor family

Semel Institute for Neuropsychiatry & Human Behavior, University of California Los Angeles, Los Angeles, CA, USA Shirley and Stefan Hatos Center for Neuropharmacology, UCLA, Los Angeles, CA, USA Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université de Strasbourg, Illkirch, France.
British Journal of Pharmacology (Impact Factor: 4.84). 06/2012; 167(5):960-9. DOI: 10.1111/j.1476-5381.2012.02075.x
Source: PubMed


The classic model of GPCR activation proposed that all agonists induce the same active receptor conformation. However, research over the last decade has shown that GPCRs exist in multiple conformations, and that agonists can stabilize different active states. The distinct receptor conformations induced by ligands result in distinct receptor-effector complexes, which produce varying levels of activation or inhibition of subsequent signalling cascades. This concept, referred to as ligand-directed signalling or biased agonism has important biological and therapeutic implications. Opioid receptors are G(i/o) GPCRs and regulate a number of important physiological functions, including pain, reward, mood, stress, gastrointestinal transport and respiration. A number of in vitro studies have shown biased agonism at the three opioid receptors (µ, δ and κ); however, in vivo consequences of this phenomenon have only recently been demonstrated. For the µ and δ opioid receptors, the majority of reported ligand selective behavioural effects are observed as differential adaptations to repeated drug administration. In terms of the κ opioid receptor, clear links between ligand-selective signalling events and specific in vivo responses have been recently characterized. Drugs for all three receptors are either already used or are being developed for clinical applications. There is clearly a need to better characterize the specific events that occur following agonist stimulation and how these relate to in vivo responses. This understanding could eventually lead to the development of tailor-made pharmacotherapies where advantageous drug effects can be selectively targeted over adverse effects.

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    • "Receptor localization within the lipid rafts after agonist binding can promote G protein coupling or recruitment of other intracellular regulatory proteins [40,41]. Over the past years, increased attention has been drawn to the understanding of intracellular signaling pathways that mediate the therapeutic and/or adverse effects of opioid agonists acting at the MOP receptor [42-44]. In vitro and in vivo studies demonstrate that different opioids can initiate distinct cellular and physiological responses downstream of receptor activation [40,42]. "
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    ABSTRACT: Background Opioid analgesics are the most effective drugs for the treatment of moderate to severe pain. However, they also produce several adverse effects that can complicate pain management. The μ opioid (MOP) receptor, a G protein-coupled receptor, is recognized as the opioid receptor type which primarily mediates the pharmacological actions of clinically used opioid agonists. The morphinan class of analgesics including morphine and oxycodone are of main importance as therapeutically valuable drugs. Though the natural alkaloid morphine contains a C-6-hydroxyl group and the semisynthetic derivative oxycodone has a 6-carbonyl function, chemical approaches have uncovered that functionalizing position 6 gives rise to a range of diverse activities. Hence, position 6 of N-methylmorphinans is one of the most manipulated sites, and is established to play a key role in ligand binding at the MOP receptor, efficacy, signaling, and analgesic potency. We have earlier reported on a chemically innovative modification in oxycodone resulting in novel morphinans with 6-acrylonitrile incorporated substructures. Results This study describes in vitro and in vivo pharmacological activities and signaling of new morphinans substituted in position 6 with acrylonitrile and amido functions as potent agonists and antinociceptive agents interacting with MOP receptors. We show that the presence of a 6-cyano group in N-methylmorphinans has a strong influence on the binding to the opioid receptors and post-receptor signaling. One 6-cyano-N-methylmorphinan of the series was identified as the highest affinity and most selective MOP agonist, and very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, this MOP agonist showed to be greatly effective against thermal and chemical nociception in mice with marked increased antinociceptive potency than the lead molecule oxycodone. Conclusion Development of such novel chemotypes by targeting position 6 provides valuable insights on ligand-receptor interaction and molecular mode of action, and may aid in identification of opioid therapeutics with enhanced analgesic properties and fewer undesirable effects.
    Molecular Pain 07/2014; 10(1):48. DOI:10.1186/1744-8069-10-48 · 3.65 Impact Factor
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    • "However, a common feature of GPCRs is that a single receptor can interact with multiple endogenous and exogenous ligands, each of which may activate the receptor in different ways. For example, a large number of endogenous opioid neuropeptides as well as many different opiate drugs interact with opioid receptors, and different opioids and opiates result in divergent processes of receptor activation and regulation (9). Thus, the simplistic view of receptor activation and regulation has been revised by the appreciation that different agonists of the same receptor can result in distinct patterns of signaling and regulation. "
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    ABSTRACT: In addition to their role in protein degradation and digestion, proteases can also function as hormone-like signaling molecules that regulate vital patho-physiological processes, including inflammation, hemostasis, pain, and repair mechanisms. Certain proteases can signal to cells by cleaving protease-activated receptors (PARs), a family of four G protein-coupled receptors. PARs are expressed by almost all cell types, control important physiological and disease-relevant processes, and are an emerging therapeutic target for major diseases. Most information about PAR activation and function derives from studies of a few proteases, for example thrombin in the case of PAR1, PAR3, and PAR4, and trypsin in the case of PAR2 and PAR4. These proteases cleave PARs at established sites with the extracellular N-terminal domains, and expose tethered ligands that stabilize conformations of the cleaved receptors that activate the canonical pathways of G protein- and/or β-arrestin-dependent signaling. However, a growing number of proteases have been identified that cleave PARs at divergent sites to activate distinct patterns of receptor signaling and trafficking. The capacity of these proteases to trigger distinct signaling pathways is referred to as biased signaling, and can lead to unique patho-physiological outcomes. Given that a different repertoire of proteases are activated in various patho-physiological conditions that may activate PARs by different mechanisms, signaling bias may account for the divergent actions of proteases and PARs. Moreover, therapies that target disease-relevant biased signaling pathways may be more effective and selective approaches for the treatment of protease- and PAR-driven diseases. Thus, rather than mediating the actions of a few proteases, PARs may integrate the biological actions of a wide spectrum of proteases in different patho-physiological conditions.
    Frontiers in Endocrinology 05/2014; 5:67. DOI:10.3389/fendo.2014.00067
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    ABSTRACT: Twelve years after the publication of the first crystal structure of a G-protein-coupled receptor (GPCR), experimental crystal structures of the four opioid receptor subtypes have made their entrance into the literature in the most extraordinary way, that is, all at once. Not only do these crystal structures contribute unprecedented molecular details of opioid ligand binding and specificity, but they also represent important tools for structure-based approaches to guide the discovery of safer and more efficient opioid therapeutics. We provide here an overview of these latest breakthroughs in the structural biology of GPCRs with a focus on differences and similarities between the four opioid receptor structures, as well as their limitations, in the context of challenges for translation of this new knowledge from bench to bedside.
    Trends in Pharmacological Sciences 11/2012; 34(1). DOI:10.1016/ · 11.54 Impact Factor
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