Magnesium and the magnesium transporter UEX regulate sleep via Ca²⁺-dependent CREB signaling and a CNK-ERK pathway

Magnesium and its related preparations are already in medical use and have recognized therapeutic effects on sleep disorders. However, its underlying molecular mechanisms remain unclear. Here, using Drosophila as a model, we found that RNAi-mediated knockdown of Uex, the homologous gene of magnesium transporters of the Cyclin M family (CNNM) causes increased daily total sleep. Ectopic-expression of CNNM1 can rescue the sleep phenotype in Uex knockdown flies. UEX exhibits rhythmic oscillations in the brain and affects the efflux of cellular Mg²⁺. Knockdown of Uex in the nervous system influences Ca²⁺-mediated CREB signaling and neuroplasticity. Additionally, Uex physically interacts with CNK, the upstream regulator of ERK pathway. Similar effects on sleep are observed with knockdown of Cnk in flies. We propose that the UEX regulates sleep through its downstream Ca²⁺-dependent CREB signaling and a CNK-ERK pathway. Our findings may provide new insight into mechanisms of magnesium and magnesium transporter related sleep disorder.