Temporal patterns of melanopsin-evoked calcium signaling engage NF-κB-associated transcriptional and phosphoproteomic responses

Cells use oscillatory calcium (Ca 2+ ) signals to regulate diverse biological processes, with temporal dynamics providing a potential layer of intracellular information. We used optogenetic activation of the Gαq-coupled photoreceptor melanopsin to impose defined slow or fast temporal stimulation patterns in human non-excitable cells, evoking oscillatory Ca 2+ -associated signaling while preserving receptor-proximal signaling. Fast, regular melanopsin stimulation induced stronger nuclear factor κB (NF-κB)-associated tumor necrosis factor ( TNF ) and interleukin-8 ( IL8 ) expression than temporally irregular stimulation, while TNF and IL8 showed partly distinct responses to stimulation frequency. Transcriptomic analysis identified an MYC-associated gene expression program despite unchanged MYC transcript levels. Integration of transcriptomic and phosphoproteomic datasets identified candidate kinase networks involving PRKDC, CHEK2, and ATM, potentially linking temporally patterned signaling to cell-cycle and stress-response pathways. Together, these findings show that distinct temporal patterns of melanopsin-evoked signaling are associated with distinct transcriptional and phospho-signaling responses, highlighting temporal dynamics as a feature of intracellular information processing.