The precise shape of action potentials in cortical neurons is a key determinant of action potential-dependent Ca2+ influx, as well as of neuronal signaling, on a millisecond scale. In cortical neurons, Ca2+-sensitive K+ channels, or BK channels (BKChs), are crucial for action potential termination, but the precise functional interplay between Ca2+ channels and BKChs has remained unclear. In this study, we investigate the mechanisms allowing for rapid and reliable activation of BKChs by single action potentials in hippocampal granule cells and the impact of endogenous Ca2+ buffers. We find that BKChs are operated by nanodomains of single Ca2+ channels. Using a novel approach based on a linear approximation of buffered Ca2+ diffusion in microdomains, we quantitatively analyze the prolongation of action potentials by the Ca2+ chelator BAPTA. This analysis allowed us to estimate that the mean diffusional distance for Ca2+ ions from a Ca2+ channel to a BKCh is approximately 13 nm. This surprisingly short diffusional distance cannot be explained by a random distribution of Ca2+ channels and renders the activation of BKChs insensitive to the relatively high concentrations of endogenous Ca2+ buffers in hippocampal neurons. These data suggest that tight colocalization of the two types of channels permits hippocampal neurons to regulate global Ca2+ signals by a high cytoplasmic Ca2+ buffer capacity without affecting the fast and brief activation of BKChs required for proper repolarization of action potentials.