Terminology summary
Spatial/Location bias: The observation of biased GPCR
signaling through the same transducer in different locations that
results in distinct signaling responses. This GPCR signal may originate
from different compartments or may be from the same compartment but then
result in the trafficking of transducers to different compartments
(Masuho, Skamangas, Muntean & Martemyanov, 2021).
Special recommendation for low efficacy
agonists
Problem: A compound may have apparent bias (yet show strong
functional selectivity) arising from low efficacy in one pathway,
leading to the absence of response in that pathway. This can erroneously
be interpreted to mean that this response will also never appear in
other (more sensitive) tissues, which may or may not be the case.
Calculating bias factors with such data is not helpful (due to the large
errors associated with essentially zero signaling in one assay).
Recommendation 13: To avoid misleading conclusions based on low
efficacy, we recommend investigating the rank order i.e., normalizing
within the transducers for each ligand without referencing to other
ligands. Only a transducer/pathway rank order change would constitute
biased signaling. For example, if ligands A and B share rank order
Gs>Gq>>arrestin
they are not biased relative to each other. However, if a third ligand,
C differs e.g.
arrestin>Gq>>Gs,
it is biased relative to A and B.
Furthermore, bias quantification should be considered together with the
quantified strength of intrinsic efficacy of ligands in the particular
relevant signaling pathways. This is because organ sensitivity and
relative intrinsic efficacy differences have a large influence on a
low-efficacy (for some pathways) ligand which may appear to be very
functionally selective in some organs. This may lead to the surprising
appearance of a signal in a more sensitive organ.
Disclaimer: Lack of response in a low efficacy pathway does not
preclude the antagonism of the natural agonist for that pathway. Thus, a
physiological bias can be produced by a synthetic ligand’s combined own
response (e.g. full agonism in pathway 1) and blockade of the endogenous
response (e.g. partial agonist in pathway 2).