Research Topic

GPCR Functional Selectivity in Health and Disease

About this Research Topic

G protein-coupled receptors (GPCRs) regulate a vast array of physiological processes in both health and disease, and are currently the largest class of druggable receptors in the human genome. Activation of these receptors leads to a host of downstream signaling effects. While most agonists will cause activation of all of the possible signaling cascades utilized by a particular receptor with similar efficacies, it is now well-established that some agonists have the ability to preferentially activate only a subset of the available signaling mechanisms of the receptor. This phenomenon is known as functional selectivity or biased signaling, and a number of biased compounds have been identified for a variety of GPCRs.

An understanding of how ligands can bias GPCRs towards a subset of signaling pathways may lead to a greater understanding of both physiology and pathophysiology, and may also improve the therapeutic profile of GPCR targeted drugs by decreasing receptor mediated side effects, while maintaining the activation of signaling pathways linked to therapeutic benefit. This approach may provide breakthroughs for rationally designing and creating improved GPCR targeted medications. For example, evidence from animal studies suggest dopamine and serotonin receptor β-arrestin-biased compounds could be useful for the treatment of schizophrenia and mood disorders. However, caution needs to be exercised when interpreting in vitro and animal model data, as these systems may not recapitulate the in vivo cellular milieu or human physiology which may affect the pharmacological profile of these biased ligands. Excitingly, recent translational human studies have demonstrated the design and testing of biased μ-opioid receptor agonists as novel analgesics, and additional biased agonists for other receptors are currently in clinical trials. Therefore, the promise and therapeutic potential of harnessing GPCR functional selectivity is now beginning to enter clinical evaluation.

The recent explosion of GPCR crystal and CryoEM structures in active and inactive states, bound to either G proteins or β-arrestin, or bound to functionally selective ligands should greatly aid in understanding the structural basis of signaling bias. In addition, further information as to the global signaling profiles of GPCR ligands will be extremely useful for understanding their potential therapeutic and side-effect profiles. Most studies of functional selectivity focus on two main signaling pathways, G protein activation or β-arrestin recruitment. However, GPCRs can modulate a plethora of other signaling pathways, and more extensive studies of how biased compounds modulate these pathways will help advance the field.

With this research topic, we aim to bring together manuscripts dealing with all aspects of this emerging field. Contributions of original research addressing the identification and pharmacological profiles of new biased ligands, molecular mechanisms of bias, structural aspects governing bias in GPCRs, novel assays and model systems used to study functional selectivity, and studies addressing the physiological effects of functionally selective ligands are of particular interest. However, we welcome all research and topics that are related to the study of GPCR functional selectivity.


Keywords: GPCRs, biased signaling, functional selectivity, drug discovery, signal transduction


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

G protein-coupled receptors (GPCRs) regulate a vast array of physiological processes in both health and disease, and are currently the largest class of druggable receptors in the human genome. Activation of these receptors leads to a host of downstream signaling effects. While most agonists will cause activation of all of the possible signaling cascades utilized by a particular receptor with similar efficacies, it is now well-established that some agonists have the ability to preferentially activate only a subset of the available signaling mechanisms of the receptor. This phenomenon is known as functional selectivity or biased signaling, and a number of biased compounds have been identified for a variety of GPCRs.

An understanding of how ligands can bias GPCRs towards a subset of signaling pathways may lead to a greater understanding of both physiology and pathophysiology, and may also improve the therapeutic profile of GPCR targeted drugs by decreasing receptor mediated side effects, while maintaining the activation of signaling pathways linked to therapeutic benefit. This approach may provide breakthroughs for rationally designing and creating improved GPCR targeted medications. For example, evidence from animal studies suggest dopamine and serotonin receptor β-arrestin-biased compounds could be useful for the treatment of schizophrenia and mood disorders. However, caution needs to be exercised when interpreting in vitro and animal model data, as these systems may not recapitulate the in vivo cellular milieu or human physiology which may affect the pharmacological profile of these biased ligands. Excitingly, recent translational human studies have demonstrated the design and testing of biased μ-opioid receptor agonists as novel analgesics, and additional biased agonists for other receptors are currently in clinical trials. Therefore, the promise and therapeutic potential of harnessing GPCR functional selectivity is now beginning to enter clinical evaluation.

The recent explosion of GPCR crystal and CryoEM structures in active and inactive states, bound to either G proteins or β-arrestin, or bound to functionally selective ligands should greatly aid in understanding the structural basis of signaling bias. In addition, further information as to the global signaling profiles of GPCR ligands will be extremely useful for understanding their potential therapeutic and side-effect profiles. Most studies of functional selectivity focus on two main signaling pathways, G protein activation or β-arrestin recruitment. However, GPCRs can modulate a plethora of other signaling pathways, and more extensive studies of how biased compounds modulate these pathways will help advance the field.

With this research topic, we aim to bring together manuscripts dealing with all aspects of this emerging field. Contributions of original research addressing the identification and pharmacological profiles of new biased ligands, molecular mechanisms of bias, structural aspects governing bias in GPCRs, novel assays and model systems used to study functional selectivity, and studies addressing the physiological effects of functionally selective ligands are of particular interest. However, we welcome all research and topics that are related to the study of GPCR functional selectivity.


Keywords: GPCRs, biased signaling, functional selectivity, drug discovery, signal transduction


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Submission Deadlines

22 January 2021 Abstract
11 June 2021 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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Topic Editors

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Submission Deadlines

22 January 2021 Abstract
11 June 2021 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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