This proposal will examine whether signaling modules serve to co-localize intracellular messengers with potassium channels of the ether-a-go-go (EAG) family by determining the physiological importance of EAG-associated signaling modules in the physiology and behavior of Drosophila. The role of signaling modules in the regulation of EAG currents will be examined (a) by co-expressing individual components in heterologous expression systems and examining the resulting currents using voltage clamp and patch clamp techniques, and (b) by electrophysiological recordings of nerve and muscle activity at the larval neuromuscular junction. Recordings from normal flies will be compared to those obtained from mutants in which components of the signaling modules have been deleted or the normal associations disrupted. The consequences of observed electrophysiological defects for hyperexcitability and other behaviors, specifically learning as assayed using a courtship conditioning assay, will also be examined. In addition to linking mechanisms of channel modulation to changes in behavior, these studies will provide evidence for one possible mechanism by which the specificity of action of intracellular enzymes can be achieved. Once understood, this mechanism can be used as a target for therapeutic agents that will be more specific than those currently employed in the treatment of a number of psychological and neuromuscular disorders.
| Hegle, Andrew P; Marble, Daniel D; Wilson, Gisela F (2006) A voltage-driven switch for ion-independent signaling by ether-a-go-go K+ channels. Proc Natl Acad Sci U S A 103:2886-91 |
| Marble, Daniel D; Hegle, Andrew P; Snyder 2nd, Eric D et al. (2005) Camguk/CASK enhances Ether-a-go-go potassium current by a phosphorylation-dependent mechanism. J Neurosci 25:4898-907 |
| Wang, Zheng; Wilson, Gisela F; Griffith, Leslie C (2002) Calcium/calmodulin-dependent protein kinase II phosphorylates and regulates the Drosophila eag potassium channel. J Biol Chem 277:24022-9 |
