AbstractIt is widely assumed that inositol trisphosphate (IP₃) and ryanodine (Ry) receptors share the same Ca²⁺ pool in central mammalian neurons. We now demonstrate that in hippocampal CA1 pyramidal neurons IP₃- and Ry-receptors are associated with two functionally distinct intracellular Ca²⁺ stores, respectively. While the IP₃-sensitive Ca²⁺ store refilling requires Orai2 channels, Ry-sensitive Ca²⁺ store refilling involves voltage-gated Ca²⁺ channels (VGCCs). Our findings have direct implications for the understanding of function and plasticity in these central mammalian neurons.