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).