AMPK regulates BK-channel current in CA1 hippocampal neurons

Abstract

AMP-activated protein kinase (AMPK) is a fundamental energy sensor fine-tuning cellular activity based on ATP availability. On the other hand, BK-channel current is tightly regulated by leptin, which in turn regulates neuronal excitability by modulating ion channels such as the BK-channel. However, this mechanism remains unclear to date. In this work we aimed to determine whether AMPK mediates the leptin regulation on BK-channel. We hypothesized that leptin regulation of BK-channel through AMPK underlies the modulating changes in neuronal excitability of CA1 hippocampal neurons. By using patch-clamping methods on CA1 pyramidal neurons in brain slices and biochemical reagents, we found that AMPK activation with AICAR inhibits BK-channel current, while AMPK inhibition with Compound C enhances BK-channel activity. Remarkably, AMPK activation reverses BK-channel current enhanced by leptin supporting an AMPK-dependent metabolic regulation of BK. Accordingly, current-clamp experiments revealed that AMPK manipulations significantly affect leptin responses on CA1 neuronal firing. These results support AMPK as a key mediator of the interplay between leptin and neuronal excitability, readily integrating metabolic signals with the computing state of firing outputs in CA1 hippocampal neurons.