Cook, D.G., Li, X., Cherry, S. D., and Cantrell, A. R. Presenilins 1 and 2 (PS1 and PS2, respectively) play a critical role in mediating -secretase cleavage of the Amyloid Precursor Protein (APP). Numerous mutations in the presenilins are known to cause early-onset familial Alzheimer's disease (FAD). In addition, it is well established that PS1-deficiency leads to altered intracellular Ca²⁺ homeostasis involving endoplasmic reticulum Ca²⁺ stores. However, there has been little evidence suggesting Ca²⁺ signals from extracellular sources are influenced by PS1. Here we report that the Ca²⁺ currents carried by voltage-dependent Ca²⁺ channels are increased in PS1-deficient cortical neurons. This increase is mediated by a significant increase in the contributions of L- and P-type Ca²⁺ channels to the total voltage-mediated Ca²⁺ conductance in PS1 (-/-) neurons. In addition, chelating intracellular Ca²⁺ with BAPTA produced an increase in Ca²⁺ current amplitude that was comparable to the increase caused by PS1-deficiency. In contrast to this, BAPTA had no effect on voltage-dependent Ca²⁺ conductances in PS1-deficient neurons. These data suggest that PS1-deficiency may influence voltage-gated Ca²⁺ channel function by means that involve intracellular Ca²⁺ signaling. These findings reveal that PS1 functions at multiple levels to regulate and stabilize intracellular Ca²⁺levels that ultimately control neuronal firing behavior and influence synaptic transmission.