Terminology summary
Biased ligand/signaling: In the broad context of an arbitrary
reference ligand, this term solely denotes a difference relative to the
reference ligand, which can in turn display any signaling. Hence, this
is a normalized quantity, analogous to fold potency, percent efficacy or
rank order relation. This term is receptor- and system-dependent and can
only be used after an explicit prior definition separating receptor and
system bias: e.g., “ligand L displays [recruitment/signaling/..]
bias towards pathway P1 over pathway P2 relative to reference ligand A
at receptor R in cell line C” (see section Unambiguous description of
ligand bias – experiment information).
Unbiased ligand: A ligand that stimulates pathways in a manner
indistinguishable from the reference ligand.
Pathway-biased ligands/signaling (using a pathway-balanced
reference
ligand)
When using a pathway-balanced reference ligand (typically a surrogate
but could be an endogenous ligand) the statement that a tested ligand is
biased carries the meaning that it preferentially activates one pathway
over the other (Table 1).
Recommendation 3: Our recommendation here concerns which
approaches to use to select a reference ligand which is balanced in its
signaling (a definition limited to the given investigated systems and
assays, see below). In an ideal case, the reference ligand would have
identical concentration-response curves in the compared pathways. A way
to quantify the similarity of pathway responses is to make a bias plot
of an equimolar comparison of induced activities (Figure 2). The most
balanced (least biased) ligand is then defined as the one with a slope
closest to 1.
A database of expert-curated pathway-balanced reference ligands will
soon be available in GPCRdb, and researchers can deposit their suggested
reference ligands via a standardized Excel file detailing information
about the pathways and assays to provide context-specific suggested
reference ligands
(download
link).