A β-amyloid oligomer directly modulates P/Q-type calcium currents in Xenopus oocytes.

BACKGROUND AND PURPOSE

β-amyloid (Aβ) oligomers have been implicated in the early pathophysiology of Alzheimer's disease (AD). While the precise nature of the molecular target has not been fully revealed, a number of studies have indicated that Aβ oligomers modulate neuron-specific ion channels. We recently provided evidence that Aβ oligomers suppress isolated P/Q-type calcium currents in cultured nerve cells. Using a heterologous expression system, we aimed to prove a direct effect on the membrane channel mediating such current.

EXPERIMENTAL APPROACH

The effects of a synthetically generated Aβ oligomer, Aβ globulomer, were investigated on P/Q-type currents recorded from Xenopus laevis oocytes expressing the full P/Q-type calcium channel or the pore-forming subunit only. We also examined the effects of Aβ globulomer on recombinant NMDA receptor currents. Finally, we compared the modulation by Aβ globulomer with that induced by a synthetic monomeric Aβ.

KEY RESULTS

Aβ globulomer directly and dose-dependently modulated P/Q-type calcium channels. A leftward shift of the current-voltage curve indicated that the threshold for channel opening was reduced. The effect of Aβ globulomer was also present when only the α1A subunit of the normally tripartite channel was expressed. In contrast, the monomeric Aβ had no effect on P/Q current. Also globulomer Aβ had no effect on glutamate-induced NMDA currents.

CONCLUSIONS AND IMPLICATIONS

The α1A subunit of the P/Q-type calcium channel is directly modulated by oligomeric Aβ. Threshold reduction as well as an increase in current at synaptic terminals may facilitate vesicle release and could trigger excitotoxic events in the brains of patients with AD.