A cellular perspective of bias at G protein-coupled receptors

Abstract

G protein-coupled receptors (GPCRs) modulate cell function over short- and long-term timescales. GPCR signaling depends on biochemical parameters that define the what, when, and where of receptor function: what proteins mediate and regulate receptor signaling, where within the cell these interactions occur, and how long these interactions persist. These parameters can vary significantly depending on the activating ligand. Collectivity, differential agonist activity at a GPCR is called bias or functional selectivity. Here we review agonist bias at GPCRs with a focus on ligands that show dramatically different cellular responses from their unbiased counterparts.

Keywords: GPCR; agonist bias; desensitization; signaling.

FIGURE 1

Cellular dimensions of GPCR function. Different ligands acting at the same receptor can alter the “what,” “where,” and “when” parameters of GPCR function. Panel 1 shows an extracellular agonist (orange) activating a GPCR (purple) and subsequent coupling to intracellular proteins (red and blue). Panel 2 highlights intracellular locations including endosomes (magenta) and Golgi (green) where GPCRs may function. Panel 3 provides a hypothetical example comparing activity of two ligands (black and red traces). Observed efficacy (y‐axis) can be dependent on when (x‐axis) an assay is performed. Ligands which show agonist bias, location bias, or kinetic bias can change these parameters compared to their unbiased counterparts. Panel 2 was adapted from Lobingier and von Zastrow 2019. ¹⁰