A secondary pathway following G-protein signal transduction is characterized by βarrestin binding, which sterically inhibits further G protein activation . We measured 5HT2C activity in response to ligand binding by characterizing the response of this pathway. The TANGO assay is based upon an engineered 5HT2C fusion protein with a cleavable C-terminal transcription factor. Upon ligand binding and recruitment of a protease-tagged β-arrestin. The intracellular C-terminal transcription factor is released, resulting in the transcriptional output of the reporter gene.