Sleep pressure accumulates in a voltage-gated lipid peroxidation memory

Voltage-gated potassium (K_V) channels contain cytoplasmically exposed β-subunits^1-5 whose aldo-keto reductase activity^6-8 is required for the homeostatic regulation of sleep⁹. Here we show that Hyperkinetic, the β-subunit of the K_V1 channel Shaker in Drosophila⁷, forms a dynamic lipid peroxidation memory. Information is stored in the oxidation state of Hyperkinetic's nicotinamide adenine dinucleotide phosphate (NADPH) cofactor, which changes when lipid-derived carbonyls^10-13, such as 4-oxo-2-nonenal or an endogenous analogue generated by illuminating a membrane-bound photosensitizer^9,14, abstract an electron pair. NADP⁺ remains locked in the active site of K_Vβ until membrane depolarization permits its release and replacement with NADPH. Sleep-inducing neurons^15-17 use this voltage-gated oxidoreductase cycle to encode their recent lipid peroxidation history in the collective binary states of their K_Vβ subunits; this biochemical memory influences-and is erased by-spike discharges driving sleep. The presence of a lipid peroxidation sensor at the core of homeostatic sleep control^16,17 suggests that sleep protects neuronal membranes against oxidative damage. Indeed, brain phospholipids are depleted of vulnerable polyunsaturated fatty acyl chains after enforced waking, and slowing the removal of their carbonylic breakdown products increases the demand for sleep.