Apolipoprotein E4 inhibits large conductance Ca 2+ ‐activated K + channels in membrane patches from hippocampal neurons

In order to clarify the possible action of apolipoprotein E4 (apoE4) on neuronal functions and to understand the proposed apoE4‐induced neurotoxicity, we investigated the effects of apoE4 on the large conductance Ca 2+ ‐activated K + (BK) channels in the inside‐out membrane patches excised from acutely dissociated rat hippocampal CA1 neurons. Results The mean conductance of BK channels was 113.6±28.8pS (n=15) or 161.4±31.9pS (n=5) in asymmetrical ([K + ] i /[K + ] o =140/5mM) or symmetrical ([K + ] i /[K + ] o =140/140mM) K + solution, respectively, and the reversal potential was −59.4mV in asymmetrical K + solution, which is close to the K + equilibrium potential. The open probability (P o ) of BK channels increased with the increase of [Ca 2+ ] i and membrane depolarization, while application of 20mM TEA in external solution completely blocked the activities of these channels. After application of apoE4 (0.5mM) to bath solution, the mean P o and open frequency of BK channels decreased by 95.1±16.8% (n=10, P<0.01) and 81.5±24.2% (n=10, P<0.01), respectively; and the mean open time of BK channels decreased by 71.3±22.1% (n=10, P<0.01), while the mean current amplitude of BK channels was not affected by the application of apoE4. The suppressive action of apoE4 on BK channels was reversible in most of the membrane patches. The present studies suggest that BK channel might be one of the action sites of apoE4 in hippocampal neurons, and the functional alteration of BK channel might play an important role in the mechanism of apoE4‐induced neurotoxicity, and thus in the pathogenesis of AD.