Dendritic spines are thought to compartmentalize second messengers like Ca2+. The notion of isolated spine signaling, however, was challenged by the recent finding that under certain conditions mobile endogenous Ca(2+)-binding proteins may break the spine limit and lead to activation of Ca(2+)-dependent dendritic signaling cascades. Since the size of spines is variable, the spine neck may be an important regulator of this spino-dendritic crosstalk. We tested this hypothesis by using an experimentally defined, kinetic computer model in which spines of Purkinje neurons were coupled to their parent dendrite by necks of variable geometry. We show that Ca2+ signaling and calmodulin activation in spines with long necks is essentially isolated from the dendrite, while stubby spines show a strong coupling with their dendrite, mediated particularly by calbindin D28k. We conclude that the spine neck geometry, in close interplay with mobile Ca(2+)-binding proteins, regulates the spino-dendritic crosstalk.