R egulation and dysregulation of intracellular calcium (Ca²⁺) signaling via the inositol 1,4,5-trisphosphate receptor (InsP₃R) has been linked to many cellular processes and pathological conditions. In the present study, addition of neuronal calcium sensor-1 (NCS-1), a high-affinity, low-capacity, calcium-binding protein, to purified InsP₃R type 1 (InsP₃R1) increased the channel activity in both a calcium-dependent and -independent manner. In intact cells, enhanced expression of NCS-1 resulted in increased intracellular calcium release upon stimulation of the phosphoinositide signaling pathway. To determine whether InsP₃R1/NCS-1 interaction could be functionally relevant in bipolar disorders, conditions in which NCS-1 is highly expressed, we tested the effect of lithium, a salt widely used for treatment of bipolar disorders. Lithium inhibited the enhancing effect of NCS-1 on InsP₃R1 function, suggesting that InsP₃R1/NCS-1 interaction is an essential component of the pathomechanism of bipolar disorder.