| Summary: | <p>The essential but enigmatic functions of sleep<sup>1,2</sup> must be reflected in molecular changes sensed by the brain’s sleep-control systems. In the fruitfly <em>Drosophila</em>, about two dozen sleep-inducing neurons<sup>3</sup> with projections to the dorsal fan-shaped body (dFB) adjust their electrical output to sleep need<sup>4</sup>, via the antagonistic regulation of two potassium conductances: the leak channel Sandman imposes silence during waking, whereas increased A-type currents through Shaker support tonic firing during sleep<sup>5</sup>. Here we show that oxidative byproducts of mitochondrial electron transport<sup>6,7</sup> regulate the activity of dFB neurons through a nicotinamide adenine dinucleotide phosphate (NADPH) cofactor bound to the oxidoreductase domain<sup>8,9</sup> of Shaker’s K<sub>V</sub>β subunit, Hyperkinetic<sup>10,11</sup>. Sleep loss elevates mitochondrial reactive oxygen species in dFB neurons, which register this rise by converting Hyperkinetic to the NADP<sup>+</sup>-bound form. The oxidation of the cofactor slows the inactivation of the A-type current and boosts the frequency of action potentials, thereby promoting sleep. Energy metabolism, oxidative stress, and sleep—three processes implicated independently in lifespan, ageing, and degenerative disease<sup>6,12,13,14</sup>—are thus mechanistically connected. K<sub>V</sub>β substrates<sup>8,15,16</sup> or inhibitors that alter the ratio of bound NADPH to NADP<sup>+</sup> (and hence the record of sleep debt or waking time) represent prototypes of potential sleep-regulatory drugs.</p>
|
|---|