In this study, we investigated the mechanism that links activation of NMDA receptors to inhibition of voltage-gated sodium channels in isolated catfish cone horizontal cells. NMDA channels were activated in voltage-clamped cells incubated in low calcium saline or dialyzed with the calcium chelator, BAPTA, to determine that calcium influx through NMDA channels is required for sodium channel modulation. To determine if calcium influx through NMDA channels triggered CICR, cells were loaded with the calcium-sensitive dye, calcium green 2, and changes in relative fluorescence were measured in response to NMDA. Responses were compared to measurements obtained when caffeine depleted stores. Voltage-clamp studies demonstrated that CICR modulated sodium channels in a similar manner as NMDA. Blocking NMDA receptors with AP-7, blocking CICR with ruthenium red, depleting stores with caffeine, or dialyzing cells with calmodulin antagonists, W-5 or peptide 290-309, all prevented sodium channel modulation. These results support the hypothesis that NMDA modulation of voltage-gated sodium channels in horizontal cells requires CICR and activation of a calmodulin dependent signaling pathway.