Biased Agonism/Antagonism of Cardiovascular GPCRs for Heart Failure Therapy.

Biased Agonism/Antagonism of Cardiovascular GPCRs for Heart Failure Therapy. Int Rev Cell Mol Biol. 2018;339:41-61 Authors: Desimine VL, McCrink KA, Parker BM, Wertz SL, Maning J, Lymperopoulos A 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...
Source: International Review of Cell and Molecular Biology - Category: Cytology Authors: Tags: Int Rev Cell Mol Biol Source Type: research