Terminology summary
Temporal effect: The effect on a measured response due to the choice of time point at which a response is recorded. Apparent biases can occur simply because the kinetics of the response is different between two pathways for two different ligands. These time effects include effects of the binding kinetics (kon and koff), time course of the biological response measured and time domain of the assay itself (e.g. reporter gene vs ion flux).

Spatial/Location Bias: Signaling with different efficacies from different cellular compartments

GPCRs have been shown to signal from a wide range of cellular compartments other than the plasma membrane, including endosomes, the Golgi and the nucleus (Crilly & Puthenveedu, 2021; Jong, Harmon & O’Malley, 2019). This signaling can be from different transducers, such as β-arrestins (Luttrell et al., 2001), Gα subunits (Feinstein et al., 2011; Irannejad et al., 2017), and Gβγ subunits (Masuho, Skamangas, Muntean & Martemyanov, 2021). With this has come the realization that signaling from the same transducer from different compartments can have distinct outcomes; for example, cAMP evolution from endosomes but not the plasma membrane promotes gene transcription (Tsvetanova & von Zastrow, 2014). This phenomenon of GPCR signaling through the same transducer in different locations producing distinct signaling responses has been referred to as spatial or location bias.
Recommendation 12: For assays of signaling from different cellular compartments, the specific biosensors and tags used for monitoring compartment-specific signaling should be described. The specific cell types used in assays should also be mentioned, as some cell types lack transporters, such as OCT3/SLC22A3, required for the trafficking of hydrophilic small-molecule ligands that cannot cross the plasma membrane (Irannejad et al., 2017). Ligands that have altered characteristics, e.g., permeability, through chemical modification should be fully described with respect to their signaling from different compartments (Jensen et al., 2017).