Presenilin 1 deficiency alters the activity of voltage-gated Ca2+ channels in cultured cortical neurons

被引:10
作者
Cook, DG
Li, XF
Cherry, SD
Cantrell, AR
机构
[1] Univ Tennessee, Hlth Sci Ctr, Dept Anat & Neurobiol, Memphis, TN 38163 USA
[2] GRECC, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA
[3] Univ Washington, Sch Med, Div Gerontol & Geriatr Med, Dept Med, Seattle, WA 98195 USA
关键词
D O I
10.1152/jn.00745.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Cook, David G., Xiaofan Li, Sheree D. Cherry, and Angela R. Cantrell. Presenilin 1 deficiency alters the activity of voltage-gated Ca2+ channels in cultured cortical neurons. J Neurophysiol 94: 4421-4429, 2005. First published September 7, 2005; doi: 10.1152/jn.00745.2005. Presenilins 1 and 2 (PS1 and PS2, respectively) play a critical role in mediating gamma-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.
引用
收藏
页码:4421 / 4429
页数:9
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