Effects of amyloid-β peptides on voltage-gated L-type Ca(V)1.2 and Ca(V)1.3 Ca(2+) channels

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(V)1.2, and surprisingly little is known about the involvement of Ca(V)1.3 in Aβ-induced neuronal toxicity. In the present study, we examined the expression patterns of Ca(V)1.3 after Aβ(25-35) exposure for 24 h and compared them with the expression patterns of Ca(V)1.2. The expression levels of Ca(V)1.3 were not significantly changed by Aβ(25-35) at both the mRNA levels and the total protein level in cultured hippocampal neurons. However, surface protein levels of Ca(V)1.3 were significantly increased by Aβ(25-35), but not by Aβ(35-25). We next found that acute treatment with Aβ(25-35) increased Ca(V)1.3 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(V)1.2 or Ca(V)1.3 α(1) subunits. These results show that Aβ(25-35) chronically or acutely upregulates Ca(V)1.3 in the rat hippocampal and human kidney cells (HEK293). This suggests that Ca(V)1.3 has a potential role along with Ca(V)1.2 in the pathogenesis of Alzheimer's disease.