Voltage-gated ion channels are essential for electrical signaling in neurons and other excitable cells. Among them, voltage-gated sodium and calcium channels are four-domain proteins, and ion selectivity is strongly influenced by a ring of amino acids in the pore regions of these channels. Sodium channels contain a DEKA motif (i.e., amino acids D, E, K, and A at the pore positions of domains I, II, III, and IV, respectively), whereas voltage-gated calcium channels contain an EEEE motif (i.e., acidic residues, E, at all four positions). Recently, a novel family of ion channel proteins that contain an intermediate DEEA motif has been found in a variety of invertebrate species. However, the physiological role of this new family of ion channels in animal biology remains elusive. DSC1 in Drosophila melanogaster is a prototype of this new family of ion channels. In this study, we generated two DSC1 knockout lines using ends-out gene targeting via homologous recombination. DSC1 mutant flies exhibited impaired olfaction and a distinct jumpy phenotype that is intensified by heat shock and starvation. Electrophysiological analysis of the giant fiber system (GFS), a well-defined central neural circuit, revealed that DSC1 mutants are altered in the activities of the GFS, including the ability of the GFS to follow repetitive stimulation (i.e., following ability) and response to heat shock, starvation, and pyrethroid insecticides. These results reveal an important role of the DSC1 channel in modulating the stability of neural circuits, particularly under environmental stresses, likely by maintaining the sustainability of synaptic transmission.