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

Abstract

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.

Functionally Validating Evolutionary Conserved Risk Genes for Parkinson’s Disease in Drosophila melanogaster

“…Both genes are widely expressed in the adult fly [ 39 ], with CtsB1 encoding a cysteine protease, and CG33181 encoding a Mg + solute carrier. Recently, knockdown of a magnesium transporter ( Uex ) in a fly model was shown to alter sleep behaviours, likely through a calcium-dependent signalling pathway [ 44 ], linking back to the molecular biology of MICU3 . In humans, the cysteine protease CTSB , besides being reported as a potential risk gene for sporadic PD [ 9 , 12 , 13 ], has also been implicated as a causative factor for the development of Alzheimer’s disease through incomplete proteolytic processing of amyloid precursors [ 45 , 46 ].…”