Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

Abstract

The mammalian circadian clock in the suprachiasmatic nucleus (SCN) is very robust, able to coordinate our daily physiological and behavioral rhythms with exquisite accuracy. Simultaneously, the SCN clock is highly sensitive to environmental timing cues such as the solar cycle. This duality of resiliency and sensitivity may be sustained in part by a complex intertwining of three cellular oscillators: transcription/translation, metabolic/redox, and membrane excitability. We suggest here that one of the links connecting these oscillators may be forged from copper (Cu). Cellular Cu levels are highly regulated in the brain and peripherally, and Cu affects cellular metabolism, redox state, cell signaling, and transcription. We have shown that both Cu chelation and application induce nighttime phase shifts of the SCN clock in vitro and that these treatments affect glutamate, N‐methyl‐D‐aspartate receptor, and associated signaling processes differently. More recently we found that Cu induces mitogen‐activated protein kinase‐dependent phase shifts, while the mechanisms by which Cu removal induces phase shifts remain unclear. Lastly, we have found that two Cu transporters are expressed in the SCN, and that one of these transporters (ATP7A) exhibits a day/night rhythm. Our results suggest that Cu homeostasis is tightly regulated in the SCN, and that changes in Cu levels may serve as a time cue for the circadian clock. We discuss these findings in light of the existing literature and current models of multiple coupled circadian oscillators in the SCN.

The physiological and pathophysiological roles of copper in the nervous system

“…Intriguingly, copper may play an important role in the regulation of circadian rhythms. The copper chaperone and transporter Atox1 (Lee et al, 2013) is expressed rhythmically in the SCN, as is ATP7A (Yamada & Prosser, 2020). Additionally, electrophysiological studies in acute SCN slices from mice demonstrated that modulation of copper availability can shift circadian clock phase.…”

“…Unlike copper chelation however, these circadian phase shifts were independent of NMDAR activation (Yamada & Prosser, 2014). Yamada and Prosser (2020) suggest that these results may best be explained by biphasic effects of copper in the SCN where too little or too much copper can phase‐shift the SCN clock and activate or inhibit distinct signalling pathways.…”

Multi-Modal Regulation of Circadian Physiology by Interactive Features of Biological Clocks

“…This partly explains how intracellular Ca 2+ generates and maintains circadian rhythms in the mouse SCN and behavioral rhythms in flies [ 224 , 236 , 237 , 238 ]. As with Ca 2+ , Cu 2+ was also found to induce nighttime phase shifts of the SCN clock in a mitogen-activated protein kinase (MAPK)-dependent manner [ 239 ]. In line with this, Feeney et al showed that intracellular Mg 2+ exhibits robust cell-intrinsic circadian rhythms and acts as a cell-autonomous timekeeping factor to determine circadian rhythms of gene expression, ATP-dependent energy expenditure, and mTOR-mediated translation in both a human cell line and a unicellular alga [ 240 ].…”

Circadian rhythmicity and the community of clockworkers

“…Highlighting a new realm of investigation, there is evidence of a contribution of a novel factor in SCN timekeeping—namely copper (Yamada & Prosser, ). Both background literature and new experimental results raise the possibility that copper is involved in light mediated glutamatergic resetting of the SCN.…”