Functional selectivity of adenosine receptor ligands |
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Authors: | Dennis Verzijl Ad P IJzerman |
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Institution: | (1) Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands; |
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Abstract: | Adenosine receptors are plasma membrane proteins that transduce an extracellular signal into the interior of the cell. Basically
every mammalian cell expresses at least one of the four adenosine receptor subtypes. Recent insight in signal transduction
cascades teaches us that the current classification of receptor ligands into agonists, antagonists, and inverse agonists relies
very much on the experimental setup that was used. Upon activation of the receptors by the ubiquitous endogenous ligand adenosine
they engage classical G protein-mediated pathways, resulting in production of second messengers and activation of kinases.
Besides this well-described G protein-mediated signaling pathway, adenosine receptors activate scaffold proteins such as β-arrestins.
Using innovative and sensitive experimental tools, it has been possible to detect ligands that preferentially stimulate the
β-arrestin pathway over the G protein-mediated signal transduction route, or vice versa. This phenomenon is referred to as
functional selectivity or biased signaling and implies that an antagonist for one pathway may be a full agonist for the other
signaling route. Functional selectivity makes it necessary to redefine the functional properties of currently used adenosine
receptor ligands and opens possibilities for new and more selective ligands. This review focuses on the current knowledge
of functionally selective adenosine receptor ligands and on G protein-independent signaling of adenosine receptors through
scaffold proteins. |
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Keywords: | Adenosine Receptor Functional selectivity Biased signaling Arrestin Scaffold protein |
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