Presenilin 1 Deficiency Alters the Activity of Voltage-Gated Ca2+ Channels in Cultured Cortical Neurons

David G. Cook, Xiaofan Li, Sheree D. Cherry, Angela R. Cantrell


Presenilins 1 and 2 (PS1 and PS2, respectively) play a critical role in mediating γ-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 1,2-bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (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.

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