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).