The relationship between the binding of divalent metal (Me) activators Ca and Sr and the secretion of acetylcholine (ACh) was studied quantitatively at frog motor nerve terminals using conventional electrophysiological methods. Experiments were designed to evaluate the assumption that maximal secretion requires occupancy of all receptors by testing for the presence of spare Ca receptors on nerve endings. Such a receptor reserve for Ca would invalidate the simple mass action approach to ACh secretion. Experimental log [Me]-ACh secretion curves constructed to saturation for Ca Sr were consistent with the presence of spare Ca receptors. La3+ (greater than or equal to 0.5 microM) and 2-chloroadenosine (25 microM) were employed as irreversible antagonists of depolarization-secretion coupling. Despite the irreversible occlusion of a proportion of Me receptors increases in the extracellular [Ca] overcame this antagonism while increases in [Sr] did not. These results suggest that Ca can produce maximal ACh release while leaving a proportion of receptors unoccupied or spare. Further support for this contention is provided by the excellent agreement between the values of the equilibrium affinity constant for Sr calculated by methods that do or do not require the assumption of spare receptors. The equilibrium affinity constant for Ca and the efficacies (efficacy reflects the ability of the Me species once bound to evoke ACh secretion) for both Ca and Sr were determined experimentally by using the mathematical framework of receptor theory. These constants were then employed to generate theoretical curves of log [Me]-ACh secretion. The theoretical relationships were similar to the experimental results, which suggests that the motor nerve endings behaves as a pharmacological receptor for Me agonists and antagonists. It is speculated that spare Ca receptors are equivalent to spare Ca channels and the efficacy may reflect the affinity of Me for an intraterminal site associated with ACh release.