The Old and New Visions of Biased Agonism Through the Prism of Adenosine Receptor Signaling and Receptor/Receptor and Receptor/Protein Interactions
Biased signaling is a concept that has arisen in the G protein-coupled receptor (GCPR) research field, and holds promise for the development of new drug development strategies. It consists of different signaling outputs depending on the agonist’s chemical structure. Here we review the most accepted...
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Frontiers Media S.A.
2021-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2020.628601/full |
| _version_ | 1818338823951613952 |
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| author | Rafael Franco Rafael Franco Rafael Rivas‐Santisteban Rafael Rivas‐Santisteban Irene Reyes-Resina Gemma Navarro Gemma Navarro |
| author_facet | Rafael Franco Rafael Franco Rafael Rivas‐Santisteban Rafael Rivas‐Santisteban Irene Reyes-Resina Gemma Navarro Gemma Navarro |
| author_sort | Rafael Franco |
| collection | DOAJ |
| description | Biased signaling is a concept that has arisen in the G protein-coupled receptor (GCPR) research field, and holds promise for the development of new drug development strategies. It consists of different signaling outputs depending on the agonist’s chemical structure. Here we review the most accepted mechanisms for explaining biased agonism, namely the induced fit hypothesis and the key/lock hypothesis, but we also consider how bias can be produced by a given agonist. In fact, different signaling outputs may originate at a given receptor when activated by, for instance, the endogenous agonist. We take advantage of results obtained with adenosine receptors to explain how such mechanism of functional selectivity depends on the context, being receptor-receptor interactions (heteromerization) one of the most relevant and most studied mechanisms for mammalian homeostasis. Considering all the possible mechanisms underlying functional selectivity is essential to optimize the selection of biased agonists in the design of drugs targeting GPCRs. |
| first_indexed | 2024-12-13T15:17:14Z |
| format | Article |
| id | doaj.art-30cb5c87968147eabec0391b5a9a66b0 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-13T15:17:14Z |
| publishDate | 2021-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-30cb5c87968147eabec0391b5a9a66b02022-12-21T23:40:40ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-01-011110.3389/fphar.2020.628601628601The Old and New Visions of Biased Agonism Through the Prism of Adenosine Receptor Signaling and Receptor/Receptor and Receptor/Protein InteractionsRafael Franco0Rafael Franco1Rafael Rivas‐Santisteban2Rafael Rivas‐Santisteban3Irene Reyes-Resina4Gemma Navarro5Gemma Navarro6Department Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, SpainCentro de Investigación en Red, Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos iii, Madrid, SpainDepartment Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, SpainCentro de Investigación en Red, Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos iii, Madrid, SpainRG Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, GermanyCentro de Investigación en Red, Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos iii, Madrid, SpainDepartment of Biochemistry and Physiology, School of Pharmacy, University of Barcelona, Barcelona, SpainBiased signaling is a concept that has arisen in the G protein-coupled receptor (GCPR) research field, and holds promise for the development of new drug development strategies. It consists of different signaling outputs depending on the agonist’s chemical structure. Here we review the most accepted mechanisms for explaining biased agonism, namely the induced fit hypothesis and the key/lock hypothesis, but we also consider how bias can be produced by a given agonist. In fact, different signaling outputs may originate at a given receptor when activated by, for instance, the endogenous agonist. We take advantage of results obtained with adenosine receptors to explain how such mechanism of functional selectivity depends on the context, being receptor-receptor interactions (heteromerization) one of the most relevant and most studied mechanisms for mammalian homeostasis. Considering all the possible mechanisms underlying functional selectivity is essential to optimize the selection of biased agonists in the design of drugs targeting GPCRs.https://www.frontiersin.org/articles/10.3389/fphar.2020.628601/fullcAMPMAPK pathwayadenylyl cyclaseGPCRtetramerheteromer |
| spellingShingle | Rafael Franco Rafael Franco Rafael Rivas‐Santisteban Rafael Rivas‐Santisteban Irene Reyes-Resina Gemma Navarro Gemma Navarro The Old and New Visions of Biased Agonism Through the Prism of Adenosine Receptor Signaling and Receptor/Receptor and Receptor/Protein Interactions Frontiers in Pharmacology cAMP MAPK pathway adenylyl cyclase GPCR tetramer heteromer |
| title | The Old and New Visions of Biased Agonism Through the Prism of Adenosine Receptor Signaling and Receptor/Receptor and Receptor/Protein Interactions |
| title_full | The Old and New Visions of Biased Agonism Through the Prism of Adenosine Receptor Signaling and Receptor/Receptor and Receptor/Protein Interactions |
| title_fullStr | The Old and New Visions of Biased Agonism Through the Prism of Adenosine Receptor Signaling and Receptor/Receptor and Receptor/Protein Interactions |
| title_full_unstemmed | The Old and New Visions of Biased Agonism Through the Prism of Adenosine Receptor Signaling and Receptor/Receptor and Receptor/Protein Interactions |
| title_short | The Old and New Visions of Biased Agonism Through the Prism of Adenosine Receptor Signaling and Receptor/Receptor and Receptor/Protein Interactions |
| title_sort | old and new visions of biased agonism through the prism of adenosine receptor signaling and receptor receptor and receptor protein interactions |
| topic | cAMP MAPK pathway adenylyl cyclase GPCR tetramer heteromer |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2020.628601/full |
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