Abstract: The invention provides protein-based sensors which report changes at a cell surface membrane. These sensors comprise an endogenous cell surface protein having a post-translationally generated luminescer at a predetermined residue. In operation, the protein adopts one of a plurality of different interconvertable signal-dependent conformations, whereunder the luminescer provides corresponding different luminescence. The cells comprise transgenes encoding the protein sensor which is translated from such transgenes by the host cell's machinery with natural amino acids and expressed on the cell surface. After surface expression, the cell is contacted with a luminescer generating reagent which generates a luminescer at a predetermined residue of the protein. A wide variety of luminescers and chemistries for generating the selected luminescer at the target residue of the sensor protein may be used.