In the bag cell neurons of Aplysia californica, activation of a non-selective cation channel initiates an afterdischarge that results in neuropeptide secretion and egg-laying behaviour. This channel is voltage-dependent and regulated by various kinases and phosphatases. We have reported (SFN abstract 86.3, 2004) that the channel is activated by Ca2+ in excised, inside-out patches. In general, Ca2+-activation of non-selective cation channels features prominently in the regulation of excitability, yet the underlying mechanism of how Ca2+ activates these conductances is unknown. For the bag cell neuron cation channel, we observed that increasing Ca2+ shifts its voltage-dependence to more hyperpolarized potentials. Moreover, the channel was not sensitive to Ba2+, pointing to calmodulin as a putative Ca2+ sensor. Calmidazolium (10µM), a calmodulin antagonist, significantly reduced channel activity at low (1µM), medium (10µM), and high (300µM) Ca2+ compared to controls. Calmodulin binding domain (50µM) also sign...