Dendritic spines convey most excitatory input in the brain. One of their presumed functions is to compartmentalize calcium, thereby, constituting a separated signaling domain for this potent second messenger. The size of spines is dynamically adjusted in an activity-dependent manner, yet, functional consequences of these morphological changes are largely unclear. Only recently we challenged the notion of isolated spine calcium-signaling by showing that mobile endogenous calcium-binding proteins (CaBPs) can break the spine limit for calcium. In the case of neighboring co-active spines that process slow synaptic calcium signals, substantial amounts of calcium were shuttled into the dendritic shaft where calcium summed and activated dendritic downstream signaling. We hypothesized that adjusting the spine morphology could provide a powerful tool to regulate this form of spatial biochemical integration in dendrites. We tested this hypothesis by using a kinetic computer model in which spines of cerebellar Purkinje neurons were coupled to their parent dendrite by a neck of variable length and diameter. Our results show that, in the presence of the native CaBPs Calbindin-D28k and Parvalbumin, the spine neck morphology exerts a substantial influence on spino-dendritc coupling and is a major determinant of dendritic calcium summation and concomitant calmodulin activation.