About this Research Topic
G protein coupled receptors (GPCRs) are the most successful class of membrane receptor drug targets for the treatment of endocrine-related disorders. They possess a unique seven-spanning transmembrane structure which conformational changes determine receptor activation and conversion of extracellular stimuli into intracellular signaling pathways. Upon activation, membrane GPCRs undergo multiple events including, desensitization, internalization, recycling, degradation and signaling from the plasma membrane or intracellular organelles. Each of these different steps can be responsible for impaired endocrinological functions and may be possibly targeted by a drug. Over the years, distinct classes of ligands have been identified either for their ability to activate (agonists, partial agonists), inhibit (antagonist), or modulate (biased ligands) GPCRs while binding to orthosteric or allosteric sites on the receptors.
It is therefore of high interest to understand which are the molecular mechanisms that determine GPCR functions as well as the pharmacology of drugs capable of targeting such mechanisms in endocrine disorders. In this context, key elements for understanding GPCR pharmacology and for developing safer and more efficacious drugs have been identified:
- Novel transduction/signaling mechanisms: GPCRs were first associated and named thereafter to
bind and activate G protein-mediated signaling pathways. Despite that, our increasing knowledge
of GPCR pharmacology reveals that such GPCRs can modulate a plethora of signaling pathways
which can rely on but are not limited to coupling promiscuity as well as initiation of uncanonical
signaling modules.
- Functional selectivity: biased ligands presenting the unique ability to trigger one or few subsets
of signaling pathways upon GPCR activation. To date, few biased signaling have been identified
and their pharmacology remain unclear.
- Structure-relationship studies: one of the major current challenges of GPCR pharmacology, is the
inability to link ligand mediated GPCR function to a high-resolution receptor structure. This would
be helpful, for instance, to design more effective/selective drugs.
- Kinetics: ligand-induced receptor kinetics have long been neglected but recent studies have
shown how kinetics impact drug-mediated GPCR responses and how they can determine the
ultimate drug efficacy.
- Compartmentalized signaling: it is now established that GPCRs initiate signaling from several spots
inside the cell. Indeed, receptors can induce signaling modules not only at the membrane but also
at intracellular compartments such as endosomes, Golgi and others, highlighting the need to
consider such additional elements in the pharmacology of GPCRs and their ligands.
The co-editors of this Research Topic welcome original research and review articles that attempt to dispel the darkness of the aforementioned questions. Ultimately, this collection of articles will contribute to understand the molecular mechanism of GPCR-induced signal transduction and the pharmacology of their ligands, paving the way for the development of safer, more effective and side-effects free drugs.
It is therefore of high interest to understand which are the molecular mechanisms that determine GPCR functions as well as the pharmacology of drugs capable of targeting such mechanisms in endocrine disorders. In this context, key elements for understanding GPCR pharmacology and for developing safer and more efficacious drugs have been identified:
- Novel transduction/signaling mechanisms: GPCRs were first associated and named thereafter to
bind and activate G protein-mediated signaling pathways. Despite that, our increasing knowledge
of GPCR pharmacology reveals that such GPCRs can modulate a plethora of signaling pathways
which can rely on but are not limited to coupling promiscuity as well as initiation of uncanonical
signaling modules.
- Functional selectivity: biased ligands presenting the unique ability to trigger one or few subsets
of signaling pathways upon GPCR activation. To date, few biased signaling have been identified
and their pharmacology remain unclear.
- Structure-relationship studies: one of the major current challenges of GPCR pharmacology, is the
inability to link ligand mediated GPCR function to a high-resolution receptor structure. This would
be helpful, for instance, to design more effective/selective drugs.
- Kinetics: ligand-induced receptor kinetics have long been neglected but recent studies have
shown how kinetics impact drug-mediated GPCR responses and how they can determine the
ultimate drug efficacy.
- Compartmentalized signaling: it is now established that GPCRs initiate signaling from several spots
inside the cell. Indeed, receptors can induce signaling modules not only at the membrane but also
at intracellular compartments such as endosomes, Golgi and others, highlighting the need to
consider such additional elements in the pharmacology of GPCRs and their ligands.
The co-editors of this Research Topic welcome original research and review articles that attempt to dispel the darkness of the aforementioned questions. Ultimately, this collection of articles will contribute to understand the molecular mechanism of GPCR-induced signal transduction and the pharmacology of their ligands, paving the way for the development of safer, more effective and side-effects free drugs.
Keywords: GPCRs, pharmacology, endocrinology, biased signaling, receptor kinetics, structurerelationship, endosomal signaling
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