TheDrosophila ergK⁺Channel Polypeptide Is Encoded by the Seizure Locus

Abstract

The eag family of K+ channels contains three known subtypes: eag, elk, and erg. Genes representing the first two subtypes have been identified in flies and mammals, whereas the third subtype has been defined only by the human HERG gene, which encodes an inwardly rectifying channel that is mutated in some cardiac arrhythmias. To establish the predicted existence of a Drosophila gene in the erg subfamily and to learn more about the structure and biological function of channels within this subfamily, we undertook a search for the Drosophila counterpart of HERG. Here we report the isolation and characterization of the Drosophila erg gene. We show that it corresponds with the previously identified seizure (sei) locus, mutations of which cause a temperature-sensitive paralytic phenotype associated with hyperactivity in the flight motor pathway. These results yield new insights into the structure and evolution of the eag family of channels, provide a molecular explanation for the sei mutant phenotype, and demonstrate the important physiological roles of erg-type channels from invertebrates to mammals.

Functional evolution of Erg potassium channel gating reveals an ancient origin for I Kr

“…Structural analysis of Eag1 has revealed that the eag domain, which is required for slow deactivation in hsErg1 and mmErg1 (27,29), docks on the CNBHD (26). An eag domain has not been identified in DmErg and CeErg (19), suggesting that loss of eag domain function might explain fast deactivation in the DmErg-like gating phenotype. We found no evidence for an eag domain in nematode Ergs or NvErg2-5 in the verified or predicted coding sequence or genome sequence.…”

“…Temperature-sensitive mutations in the seizure locus that encodes DmErg cause bursts of uncoordinated motor output (19) suggestive of changes in subthreshold excitability. The Caenorhabditis elegans Erg ortholog (CeErg, encoded by unc-103) has not been functionally expressed, but genetic analysis demonstrates that it regulates the excitation threshold of vulva muscles in females and protractor muscles in males (20)(21)(22)(23).…”

A Drosophila behavioral mutant, down and out ( dao ), is defective in an essential regulator of Erg potassium channels

“…1B). These behavioral and electrophysiological phenotypes of dao are very similar to sei mutants, which disrupt Ergtype K + channels (3,4,(9)(10)(11). However, complementation tests revealed that dao and sei affect different genes.…”

“…Screening for behavioral mutations in Drosophila that perturb neural signaling has been an effective means of identifying key proteins and cellular pathways that regulate excitability. Particularly useful for such studies have been temperature-sensitive (ts) paralytic mutants including paralytic (para) and slowpoke (slo), which encode voltage-gated sodium channels and calcium-activated potassium channels, respectively, and seizure (sei), which encodes the Drosophila ortholog of the voltage-gated human ether-a-go-go-related gene (hERG) potassium channel (1)(2)(3)(4).…”

A Neuroprotective Function of NSF1 Sustains Autophagy and Lysosomal Trafficking inDrosophila

“…However, we found that comt; sei ts2 double mutants (Jackson et al 1985;Elkins and Ganetzky 1990;Titus et al 1997;Wang et al 1997) were no more severe than comt mutants alone when measuring lifespan, locomotor defects, or loss of DA neurons (Figure 3, C-E).…”