Visual Overview
Abstract
When studying G protein–coupled receptor (GPCR) signaling and ligand-biased agonism, at least three dimensional spaces must be considered, as follows: 1) the distinct conformations that can be stabilized by different ligands promoting the engagement of different signaling effectors and accessory regulators; 2) the distinct subcellular trafficking that can be conferred by different ligands, which results in spatially distinct signals; and 3) the differential binding kinetics that maintain the receptor in specific conformation and/or subcellular localization for different periods of time, allowing for the engagement of distinct signaling effector subsets. These three pluridimensional aspects of signaling contribute to different faces of functional selectivity and provide a complex, interconnected way to define the signaling profile of each individual ligand acting at GPCRs. In this review, we discuss how each of these aspects may contribute to the diversity of signaling, but also how they shed light on the complexity of data analyses and interpretation. The impact of phenotype variability as a source of signaling diversity, and the influence of novel and more sensitive assays in the detection and analysis of signaling pluridimensionality, is also discussed. Finally, we discuss perspectives for the use of the concept of pluridimensional signaling in drug discovery, in which we highlight future predictive tools that may facilitate the identification of compounds with optimal therapeutic and safety properties based on the signaling signatures of drug candidates.
Footnotes
- Received July 2, 2016.
- Accepted September 14, 2016.
C.M.C.-N. holds a Brazilian National Council for Scientific and Technological Development (CNPq) research fellowship, and his work on the topic of this review is supported by the Sao Paulo State Research Foundation (FAPESP) [Grant 2012/20148-0], and by the Ribeirao Preto Medical School, University of São Paulo. L.T.P.-S. holds a FAPESP postdoctoral fellowship and was a recipient of a FAPESP international fellowship for a training period of 1 year at M.B.’s laboratory. M.B. holds the Canada Research Chair in Signal Transduction and Molecular Pharmacology, and his work on the topic of this review is supported by the Canadian Institute for Health Research. C.M.C.-N. and M.B. have a joint international cooperation grant supported by FAPESP [Grant SPRINT 2015/50086-4] on the subject of this review.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|