Significance Nicotinic α7 receptors are neurotransmitter-gated ion channels that participate in cognitive, cytoprotective, and anti-inflammatory processes and have emerged as targets for neurological disorders and therapeutic drugs. They are associated with extrasynaptic volume transmission where they are exposed to low ACh concentrations and thus function with partial occupancy of their five identical binding sites. By generating α7 receptors with different numbers of functional ACh binding sites and measuring open-channel lifetimes of individual receptors, we find that occupancy of one site produces a maximal response and that the additional sites enhance agonist sensitivity. Thus, ACh occupancy of only one of five sites in α7 produces a maximal response, adapting it to extrasynaptic volume transmission in neuronal and nonneuronal cells.