Ultra long-term local intracellular Ca^<2+> dynamics in neurons responsible for the mammalian circadian clock

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Intracellular free Ca^<2+> regulates diverse cellular processes, including membrane potential, neurotransmitter release, and gene expression. To examine the cellular mechanisms underlying the generation of circadian rhythms, nucleus-targeted and untargeted cDNAs encoding a Ca^<2+>-sensitive fluorescent protein (yellow cameleon-2.1) were transfected into organotypic cultures of mouse suprachiasmatic nucleus (SCN), the primary circadian pacemaker. Circadian rhythms in cytosolic but not nuclear Ca^<2+> concentration were observed in SCN neurons. The cytosolic Ca^<2+> rhythm period matched the circadian multiple-unit-activity (MIUA)-rhythm period monitored using a multiple-electrode-array, with a mean advance in phase of 4 hours. Tetrodotoxin blocked MIUA, but not Ca^<2+> rhythms, while ryanodine and 8-bromo-cyclic ADP ribose damped both Ca^<2+> and MUA rhythms. These results demonstrate cytosolic Ca^<2+> rhythms regulated by the Ca^<2+> release from ryanodine-sensitivie stores in SCN neurons.