Potassium (K+) channels comprise a large group of proteins that play integral roles in synaptic transmission, action potential waveform and firing properties of excitable cells. In contrast to these extensive characterization of the Shaker (Sh) K+ channel family, many questions remain unanswered concerning the function and regulation of the ether-a- go-go related gene (ERG) product in cellular physiology is of interest and the role of human ERG in Long QT syndrome warrants additional investigation. Given that ion channels can be controlled at the level of transcription as well as modulated by other signalling proteins/ion channels, we are proposing to characterize dERG expression at the transcriptional level and identify trans-acting factors key in the control of dERG expression. In addition, we will utilize genetic and biochemical approaches to identify key regulatory molecules that may comprise accessory subunits of the dERG channel or are up- or downstream modulatory effects of the dERG genomic sequence flanking the dERG gene. Preliminary evidence has localized the dERG transcriptional control sites within a define genomic region and the proposed experiments will serve to identify key sites required for expression s well as the trans-acting factors responsible for spatial and temporal expression of the dERG mRNA. We will also utilize genetic screens to identify other gene products that modify dERG function and comprise either accessory subunits or regulatory molecules that affect signaling pathways regulated or modulated by dERG. Because Drosophila is one of very few organisms in which in situ genetic mutational analysis of K+ channels can be combined with both heterologous expression and in vivo physiology, these studies will permit us to elucidate new information regarding ERG K+ channel function and regulation and may shed light upon the role of ERG in cell physiology, signaling and its role in the pathophysiology of such maladies as LQT syndrome and epilepsy.
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