Mapping the sequence determinants of constitutive activity in GPCRs
G protein-coupled receptors (GPCRs) signal not only in response to ligands but also in their absence. This basal, or constitutive, activity has distinct physiological consequences and is the only functional measurement available for orphan receptors. It is also hard to compare receptors because each is reported relative to its own baseline. Here, we measure basal activity on a single scale across…
G protein-coupled receptors (GPCRs) demonstrate activity not solely in response to ligands but also without them. This constant, or constitutive, activity carries significant physiological implications and serves as the sole functional indicator for orphan receptors. Comparing receptors is challenging due to each being reported relative to its own baseline.
In this study, researchers measured basal activity on a unified scale across the entire human GPCR family. Utilizing a barcoded library encompassing all human GPCRs and a transcriptional cAMP reporter, they assessed 901 receptor constructs in a single experiment. Basal activity exhibits a continuous distribution, with many of the top-scoring patterns previously reported for ligand-independent activity, with a strong representation of orphan receptors.
The researchers subsequently subjected one receptor, GPR161, to extensive mutation and evaluated its impact on protein abundance, surface expression, and cAMP signaling. Out of the 528 mutated positions, only 10 specifically affected signaling independently of expression. Factors governing basal signaling are primarily driven by reepotro biogenesis, necessitating multiphenotype scanning for thorough analysis.
These comprehensive datasets establish a standardized scale for basal activity across the GPCR family, offering a framework for dissecting it at the residue level.
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