Na⁺/Ca²⁺ exchanger mediates cold Ca²⁺ signaling conserved for temperature-compensated circadian rhythms.

Abstract

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⁺/Ca²⁺ exchanger (NCX) mediates cold-responsive Ca²⁺ signaling important for the temperature-compensated oscillation in mammalian cells. In response to temperature decrease, NCX elevates intracellular Ca²⁺, which activates Ca²⁺/calmodulin-dependent protein kinase II and accelerates transcriptional oscillations of clock genes. The cold-responsive Ca²⁺ signaling is conserved among mice, <i>Drosophila</i>, and <i>Arabidopsis</i> The mammalian cellular rhythms and <i>Drosophila</i> 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 Ca²⁺ signaling is a common mechanism underlying temperature-compensated circadian rhythms both in eukaryotes and prokaryotes.