Autonomous circadian oscillators intrinsic to cell membranes

Circadian rhythms, originating in endogenous cellular clockworks, are the evolutionary solution that allows organisms to anticipate and synchronize their internal processes with the predictable changes in their environment on a daily basis. Across evolution, circadian oscillators share a conserved design based on delayed negative feedbacks, yet differ in their molecular implementation in prokaryotes and eukaryotes. Although eukaryotic circadian timing is conventionally assumed to originate from nuclear transcription-translation feedback loop (TTFL) clockworks, mounting evidence indicates that daily rhythms can also persist in cells devoid of such nuclear clocks, including the circadian variation of metabolism and redox state in red blood cells. Here, we demonstrate the generation of endogenous circadian oscillations through a membrane-associated post-translational feedback loop (PTFL) mechanism that operates independently of the nuclear TTFL clock and relies on the dynamic regulation of ion channel gating. This mechanism accounts for the circadian oscillations observed in potassium transport, redox state, and metabolism in anucleate red blood cells. The same membrane-associated mechanism may operate in nucleated cells as well. In circadian clock neurons, it could clarify rhythmic changes in ion channel conductances that cannot be attributed to the nuclear TTFL oscillator. Oscillations in ion fluxes directly modulate neuronal excitability, potentially giving rise to spontaneous circadian firing rhythms and synchronized bursting.