Krüppel Mediates the Selective Rebalancing of Ion Channel Expression

Abstract

SUMMARY Ion channel gene expression can vary substantially among neurons of a given type, even though neuron-type-specific firing properties remain stable and reproducible. The mechanisms that modulate ion channel gene expression and stabilize neural firing properties are unknown. In Drosophila, we demonstrate that loss of the Shal potassium channel induces the compensatory rebalancing of ion channel expression including, but not limited to, the enhanced expression and function of Shaker and slowpoke. Using genomic and network modeling approaches combined with genetic and electrophysiological assays, we demonstrate that the transcription factor Krüppel is necessary for the homeostatic modulation of Shaker and slowpoke expression. Remarkably, Krüppel induction is specific to the loss of Shal, not being observed in five other potassium channel mutants that cause enhanced neuronal excitability. Thus, homeostatic signaling systems responsible for rebalancing ion channel expression can be selectively induced after the loss or impairment of a specific ion channel.

Novel cell-free high-throughput screening method for pharmacological tools targeting K + channels

“…We still do not understand the biological roles played by many of these channels, mainly because we have not yet developed a sufficient set of pharmacological tools. Gene knockout technology has advanced our understanding to some degree, but such approaches are not good surrogates for acute pharmacology experiments because compensatory expression of a second channel that can fulfill the role of the missing first is all too common, especially given the large number and redundancy of K + channels (35,36). This paper presents an assay called LFA, to identify inhibitors and activators of K + channels.…”

Regulation of synaptic development and function by the Drosophila PDZ protein Dyschronic

“…Loss of specific ion channels in Drosophila has been shown to activate homeostatic transcriptional networks that act to balance excitability (Parrish et al, 2014;Ping and Tsunoda, 2012). In addition, the AZ T-bar itself has been theorized to function as a 'plasticity module' that can undergo structural adjustments in response to changes in synaptic input that, in turn, modify the probability of vesicle release (Wichmann and Sigrist, 2010).…”

Homeostatic Control of Presynaptic Neurotransmitter Release

“…Thus, although the point mutation does not alter the ability of the Ca V 2.1 channel to pass calcium, it may render it insensitive to low-voltage membrane modulation during presynaptic homeostasis. Second, it was previously shown that presynaptic overexpression of a potassium channel, either Shaker or Kir2.1, blocks presynaptic homeostasis (4,72,73). If increased potassium leak prevents ENaC channel-dependent depolarization of the presynaptic membrane, then this could explain why potassium channel overexpression blocks the expression of presynaptic homeostasis.…”

“…The emerging field of homeostatic plasticity can be subdivided into three areas that are defined by the way in which a cell responds to a perturbation, namely the homeostatic control of intrinsic excitability (1)(2)(3)(4)(5)(6)(7), neurotransmitter receptor expression (3,7), and presynaptic neurotransmitter release (8)(9)(10)(11)(12). Together, these areas represent a suite of mechanisms that confer stability to nervous system function.…”