Functional Characterization of the DSC1 Family of Voltage-gated Cation Channels
More than two decades ago, a putative sodium channel gene, DSC1 (Drosophila sodium channel 1), was isolated from Drosophila melanogaster using a cDNA probe encoding the eel sodium channel (Salkoff et al., 1987). The DSC1 protein shares a high sequence similarity with insect and mammalian sodium channel α-subunits. In collaboration with Al Goldin’s laboratory at UC, Irvine, we conducted molecular and functional characterization of BSC1, the cockroach orthologue of DSC1. Our study revealed that BSC1 encodes a novel voltage-gated Ca2+-selective cation channel with gating properties distinct from those of classic sodium or calcium channels (Zhou et al., 2004).
[Ca2+ refers to altered levels of ionized calcium.]
Subsequent expression of DSC1 channels in oocytes confirms that DSC1 also encodes a voltage-gated cation channel similar to the BSC1 channel (Zhang et al., 2011). Interestingly, the DSC1 family of genes is restricted to insects and several other invertebrates (Cui et al, 2012; Barzilai et al., 2012); they are not found in mammals (Zhou et al., 2004; Yu and Catterall, 2004). In this regard, the DSC1 family of ion channels represents attractive targets for future development of novel insect-selective chemicals.
To understand the physiological role of the DSC1/BSC1 channel and evaluate the potential of this family of new channels as potential targets for new selective insecticides, we generated two DSC1 knockout lines using the method of gene knockout via homologous recombination. We conducted behavioral assays and in vivo electrophysiological characterization of the giant fiber system of DSC1 knock-out mutants, suggesting that this family of cation channels plays an important role in regulating membrane excitability in vivo (Zhang et al., 2013). We are currently conducting further behavioral assays and neural circuit analyses to reach a comprehensive understanding of the role of the DSC1 family of channels in insect neurophysiology and behavior.
Another goal of this project is to determine the role of the DSC1 family of channels in insect neurotoxicology. Although the DSC1 channel is functionally distinct from the sodium channel, there is about a 50% sequence identity in the transmembrane domains between the two types of ion channels. We are currently investigating whether the DSC1 family of channels could be targets of bioactive chemicals that are related to sodium channel-targeting insecticides.