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

Abstract

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.