Location bias: A "Hidden Variable" in GPCR pharmacology.

Autor: Eiger DS; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Hicks C; Trinity College, Duke University, Durham, North Carolina, USA., Gardner J; Trinity College, Duke University, Durham, North Carolina, USA., Pham U; Department of Biochemistry, Duke University, Durham, North Carolina, USA., Rajagopal S; Department of Biochemistry, Duke University, Durham, North Carolina, USA.; Department of Medicine, Duke University, Durham, North Carolina, USA.
Jazyk: angličtina
Zdroj: BioEssays : news and reviews in molecular, cellular and developmental biology [Bioessays] 2023 Nov; Vol. 45 (11), pp. e2300123. Date of Electronic Publication: 2023 Aug 25.
DOI: 10.1002/bies.202300123
Abstrakt: G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and primarily signal through two main effector proteins: G proteins and β-arrestins. Many agonists of GPCRs promote "biased" responses, in which different cellular signaling pathways are activated with varying efficacies. The mechanisms underlying biased signaling have not been fully elucidated, with many potential "hidden variables" that regulate this behavior. One contributor is "location bias," which refers to the generation of unique signaling cascades from a given GPCR depending upon the cellular location at which the receptor is signaling. Here, we review evidence that GPCRs are expressed at and traffic to various subcellular locations and discuss how location bias can impact the pharmacologic properties and characterization of GPCR agonists. We also evaluate how differences in subcellular environments can modulate GPCR signaling, highlight the physiological significance of subcellular GPCR signaling, and discuss the therapeutic potential of exploiting GPCR location bias.
(© 2023 Wiley Periodicals LLC.)
Databáze: MEDLINE
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