A potassium channel β-subunit couples mitochondrial electron transport to sleep

Abstract

The essential but enigmatic functions of sleep1,2 must be reflected in molecular changes sensed by the brain's sleep-control systems. In Drosophila, two dozen sleep-inducing neurons3 with projections to the dorsal fan-shaped body (dFB) adjust their electrical output to sleep need4, via the antagonistic regulation of two potassium conductances: the leak channel Sandman imposes silence during waking, whereas augmented A-type currents through Shaker support tonic firing during sleep5. Here, we report that oxidative by-products of mitochondrial electron transport6,7 regulate the activity of dFB neurons through a nicotinamide adenine dinucleotide phosphate (NADPH) cofactor bound to the oxidoreductase domain8,9 of Shaker's KVβ subunit, Hyperkinetic10,11. Sleep loss elevates mitochondrial reactive oxygen species in dFB neurons, which register this rise by converting Hyperkinetic to the NADP+-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, aging, and degenerative disease6,12–14, are thus mechanistically connected. KVβ substrates8,15,16 or inhibitors capable of altering the NADP+:NADPH ratio (and hence the neurons' record of sleep debt or waking time) define novel prototypes of sleep-regulatory drugs.

Shaw and Shal voltage‐gated potassium channels mediate circadian changes in Drosophila clock neuron excitability

“…; Kempf et al . ). Phosphorylation may also be an important post‐translational means of circadian regulation of ion channel activity, with mammalian slo or BK being under phosphorylation control in the SCN (Shelley et al .…”

“…[Colour figure can be viewed at wileyonlinelibrary.com] J Physiol 597.23 and longevity. Null mutants sleep a third as long as normal flies resulting in flies with significant reductions in lifespan (Cirelli et al 2005;Bushey et al 2007;Kempf et al 2019). Phosphorylation may also be an important post-translational means of circadian regulation of ion channel activity, with mammalian slo or BK being under phosphorylation control in the SCN (Shelley et al 2013).…”

A salt-induced kinase (SIK) is required for the metabolic regulation of sleep

“…An alternative possibility is that liberated free fatty acids or their metabolites play a signaling role in regulating sleep, a mechanism that would be similar to sleep regulation by arachidonic acid metabolites in mammals [95]. Finally, a third possibility is that fatty acid catabolism biproducts such as reactive oxygen species promote sleep, as has recently been demonstrated in Drosophila [96, 97].…”

Unraveling Why We Sleep: Quantitative Analysis Reveals Abrupt Transition from Neural Reorganization to Repair in Early Development

“…Although we spend approximately a third of our life asleep, its explicit physiological and evolutionary function remains unclear with myriad hypotheses having been postulated . Two of the leading hypotheses are that sleep enables (i) the repair and clearance needed to correct and prevent neuronal damage (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(29)(30)(31)(32) and (ii) the neural reorganization necessary for learning and synaptic homeostasis (13)(14)(15)(16)(17)(18)(19)(20)(21). These hypotheses are compelling because neither of these processes can be easily achieved in waking states and there is supporting empirical evidence that they occur during sleep.…”