Fluorinated General Anesthetics Modulate Kv1.3 Potassium Channels and Interact With β-Amyloid Peptide: Is there a Link?

Abstract

There is growing evidence that, in some cases, commonly used general anesthetics may cause long-term molecular changes reminiscent of those observed in the Alzheimer's diseased brain. We investigated the effects of the anesthetic sevoflurane on the voltage-gated potassium channel Kv1.3. In the central nervous system, Kv1.3 channels are present in olfactory regions and in the dentate gyrus of the hippocampus, areas implicated in AD pathology. The expression of Kv1.3 is also up-regulated in activated microglia, suggesting its possible role in microglial response to β-amyloid peptide. Using whole-cell patch clamp recording from L929 cells stably expressing Kv1.3, we found that sevoflurane modulates biophysical properties of the Kv1.3 channel. At clinically relevant concentrations, sevoflurane biphasically alters peak current amplitude, irreversibly facilitating the current at lower voltages (EC50 ∼ 1/2 MAC) and reversibly inhibiting it at higher voltages (IC50 ∼ 1 MAC). The kinetics of the Kv1.3 current were also changed in a voltage- and dose-dependent manner. The time constants of both current activation and the slow C-type inactivation were significanly decreased, whereas current deactivation was slower at low voltages but faster at higher voltages in the presence of sevoflurane. Sevoflurane slightly increased the voltage sensitivity of Kv1.3 conductance at a clinically relevant dose. The effects of sevoflurane resemble the previously-reported effects of the exogenous β-amyloid oligomers on the same channel. Using 19F NMR, we found that, in the test tube, sevoflurane interacts with β-amyloid peptide and forms stable complexes. Furthermore, dot blot immunochemistry revealed that sevoflurane appears to facilitate the rate of cytotoxic β-amyloid oligomer formation.Thus, modulation of Kv1.3 channels by sevoflurane and its interaction with β-amyloid peptide might both enhance the progression of Alzheimer's disease. Supported by the Hillblom Foundation and NIH 1P01AG032131.