Biased Agonism/Antagonism of Cardiovascular GPCRs for Heart Failure Therapy

International Review of Cell and Molecular Biology
Victoria L DesimineAnastasios Lymperopoulos

Abstract

G protein-coupled receptors (GPCRs) are among the most important drug targets currently used in clinic, including drugs for cardiovascular indications. We now know that, in addition to activating heterotrimeric G protein-dependent signaling pathways, GPCRs can also activate G protein-independent signaling, mainly via the βarrestins. The major role of βarrestin1 and -2, also known as arrestin2 or -3, respectively, is to desensitize GPCRs, i.e., uncoupled them from G proteins, and to subsequently internalize the receptor. As the βarrestin-bound GPCR recycles inside the cell, it serves as a signalosome transducing signals in the cytoplasm. Since both G proteins and βarrestins can transduce signals from the same receptor independently of each other, any given GPCR agonist might selectively activate either pathway, which would make it a biased agonist for that receptor. Although this selectivity is always relative (never absolute), in cases where the G protein- and βarrestin-dependent signals emanating from the same GPCR result in different cellular effects, pharmacological exploitation of GPCR-biased agonism might have therapeutic potential. In this chapter, we summarize the GPCR signaling pathways and their biased agonism/antagoni...Continue Reading

Citations

Jun 27, 2019·Pharmacology Research & Perspectives·Maria E SolesioAnastasios Lymperopoulos
Mar 23, 2019·International Journal of Molecular Sciences·Celina M PollardAnastasios Lymperopoulos
Jun 14, 2019·Frontiers in Pharmacology·Emiel P C van der VorstYvonne Döring
Apr 10, 2019·International Journal of Molecular Sciences·Elena De AngelisAda Popolo
Sep 17, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Wolfgang SadeeZaijie Wang
Sep 10, 2020·British Journal of Pharmacology·Daolai ZhangZhigang Xu

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