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This Article Full Text Full Text (PDF) All Versions of this Article: 94/6/4421    most recent 00745.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Cook, D. G. Articles by Cantrell, A. R. Search for Related Content PubMed PubMed Citation Articles by Cook, D. G. Articles by Cantrell, A. R.

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

¹Veterans Affairs Puget Sound Health Care System, Geriatric Research Education and Clinical Center (GRECC), Seattle, Washington; ²Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle Washington; and ³Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis Tennessee

Submitted 15 July 2005; accepted in final form 31 August 2005

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 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.