Kathiresan Natarajan, Nuriya Mukhtasimova, Cecilia Bouzat, Steven Sine (left to right), and colleagues demonstrate that, at low ACh levels, the activity of α7 nAChRs is potentiated by extracellular calcium, which binds to a pair of anionic residues at the entrance to the ligand-binding pocket. Ribbon diagrams show the position of this binding site on an α7/AChBP chimera used as a surrogate in MD simulations.