Effects of Amyloid-β peptides on voltage-gated L-Type Ca v1.2 and Ca v1.3 Ca 2+ channels

Abstract

Overload of intracellular Ca 2+ has been implicated in the pathogenesis of neuronal disorders, such as Alzheimer's disease. Various mechanisms produce abnormalities in intracellular Ca 2+ homeostasis systems. L-type Ca 2+ channels have been known to be closely involved in the mechanisms underlying the neurodegenerative properties of amyloid-β (Aβ) peptides. However, most studies of L-type Ca 2+ channels in Aβ-related mechanisms have been limited to Ca v1.2, and surprisingly little is known about the involvement of Ca v1.3 in Aβ-induced neuronal toxicity. In the present study, we examined the expression patterns of Ca v1.3 after Aβ25-35 exposure for 24 h and compared them with the expression patterns of Ca v1.2. The expression levels of Ca v1.3 were not significantly changed by Aβ25-35 at both the mRNA levels and the total protein level in cultured hippocampal neurons. However, surface protein levels of Ca v1.3 were significantly increased by Aβ25-35, but not by Aβ35-25. We next found that acute treatment with Aβ25-35 increased Ca v1.3 channel activities in HEK293 cells using whole-cell patch-clamp recordings. Furthermore, using GTP pulldown and co-immunoprecipitation assays in HEK293 cell lysates, we found that amyloid precursor protein interacts with β 3 subunits of Ca 2+ channels instead of Ca v1.2 or Ca v1.3 a1 subunits. These results show that Aβ25-35 chronically or acutely upregulates Ca v1.3 in the rat hippocampal and human kidney cells (HEK293). This suggests that Ca v1.3 has a potential role along with Ca v1.2 in the pathogenesis of Alzheimer's disease. © 2011 KSMCB.