Mapping the sequence determinants of constitutive activity in GPCRs

Basal, ligand-independent activity across the human GPCR family forms a continuous distribution, with 901 receptor constructs scored on a single scale using a barcoded cAMP reporter system.

• Why it matters: Constitutive GPCR activity has distinct physiological consequences and is the only functional readout for orphan receptors, but cross-receptor comparisons are difficult when each is measured against its own baseline.
• What they did: A pooled experiment paired a barcoded library of all human GPCRs with a transcriptional cAMP reporter to score 901 constructs, then exhaustively mutated GPR161 and assessed protein abundance, surface expression, and cAMP signaling.
• The result: Across 528 mutated positions in GPR161, only 10 altered signaling independent of expression, and the resulting datasets enable residue-resolution mapping of basal signaling constraints on a common family scale.

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