Na/Ca exchanger mediates cold Ca signaling conserved for temperature-compensated circadian rhythms.

Circadian rhythms are based on biochemical oscillations generated by clock genes/proteins, which independently evolved in animals, fungi, plants, and cyanobacteria. Temperature compensation of the oscillation speed is a common feature of the circadian clocks, but the evolutionary-conserved mechanism has been unclear. Here, we show that Na/Ca exchanger (NCX) mediates cold-responsive Ca signaling important for the temperature-compensated oscillation in mammalian cells. In response to temperature decrease, NCX elevates intracellular Ca, which activates Ca/calmodulin-dependent protein kinase II and accelerates transcriptional oscillations of clock genes. The cold-responsive Ca signaling is conserved among mice, , and The mammalian cellular rhythms and behavioral rhythms were severely attenuated by NCX inhibition, indicating essential roles of NCX in both temperature compensation and autonomous oscillation. NCX also contributes to the temperature-compensated transcriptional rhythms in cyanobacterial clock. Our results suggest that NCX-mediated Ca signaling is a common mechanism underlying temperature-compensated circadian rhythms both in eukaryotes and prokaryotes.