A three-dimensional presynaptic calcium diffusion model developed to account for characteristics of transmitter release was modified to provide for binding of calcium to a receptor and subsequent triggering of exocytosis. When low affinity (20 microM) and rapid kinetics were assumed for the calcium receptor triggering exocytosis, and stimulus parameters were selected to match those of experiments, the simulations predicted a virtual invariance of the time course of transmitter release to paired stimulation, stimulation with pulses of different amplitude, and stimulation in different calcium solutions. The large temperature sensitivity of experimental release time course was explained by a temperature sensitivity of the model's final rate limiting exocytotic process. Inclusion of calcium tail currents and a saturable buffer with finite binding kinetics resulted in high peak calcium transients near release sites, exceeding 100 microM. Models with a single class of calcium binding site to the secretory trigger molecule failed to produce sufficient synaptic facilitation under this condition. When at least one calcium ion binds to a different site having higher affinity and slow kinetics, facilitation again reaches levels similar to those seen experimentally. It is possible that the neurosecretory trigger molecule reacts with calcium at more than one class of binding site.