In order to maintain functional ionic gradients across their membranes during physical and biological stresses, neurons need to adjust their electrical properties. Understanding how such physiological adjustments are made is important since disruptions in neuronal homeostasis have been implicated in various behavioral and neuronal pathologies, such as seizures and cognitive deficits, as well as in certain psychiatric conditions. Established models propose that the regulation of neuronal homeostasis requires changes in the relative abundances of potassium and sodium channels at the membrane. Yet, how these channels are regulated in response to environmental stresses such as heat is not well understood. This proposal investigates a novel posttranscriptional molecular mechanism for the regulation of neuronal homeostasis. Our proposal is based on our preliminary data, which demonstrate that pickpocket 29 (ppk29), a Drosophila Degenerin/epithelial sodium channel (DEG/ENaC), and seizure (sei), the sole fly homolog of the human Ether-alpha-go-go-Related Gene (hERG) potassium channel, are convergently transcribed from opposite DNA strands with their 3'UTRs complementing each other. Previous studies have indicated that mutations in sei cause sensitivity to heat induced seizures and paralysis due to hyperexcitability. In contrast, mutations in ppk29 lead to opposite neurophysiological and behavioral phenotypes that are consistent with a protection from heat induced seizures and paralysis. Furthermore, our data indicate that the 3'UTR of ppk29 regulates neuronal plasticity independent of its protein coding capacity. The unusual genetic architecture and the opposing neuronal and behavioral phenotypes mediated by these two functionally antagonistic channels led us to study the hypothesis that the mRNA of one ion channel can regulate the function of another opposing ion channel via the formation of 3'UTRs-dependent dsRNA leading to gene specific siRNAs, which act as a molecular regulatory mechanism underlying the homeostatic neuronal response to environmental stress.
Understanding the neuronal homeostatic response to environmental stresses such as heat is important since many cognitive deficits and neuronal pathologies such as epilepsy and febrile seizures are due to disruptions in this process. We investigate a novel molecular mechanism for neuronal homeostasis that is based on the regulation of the hERG-like voltage-gated potassium channel seizure (sei) by the ligand-gated DEG/ENaC sodium channel pickpocket 29 (ppk29) via the endogenous siRNA pathway. Since similar genetic architectures are also present in some mammalian eag-like channels, the proposed studies will have wide implications for our understanding of the role of the endogenous siRNA pathway and eag-like potassium channels in regulating neuronal excitability in response to environmental heat stress such as in the case of febrile seizures in children.
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