tipE regulates Na+-dependent repetitive firing in Drosophila neurons

The tipE gene, originally identified by a temperature-sensitive paralytic mutation in Drosophila, encodes a transmembrane protein that dramatically influences sodium channel expression in Xenopus oocytes. There is evidence that tipE also modulates sodium channel expression in the fly; however, its role in regulating neuronal excitability remains unclear. Here we report that the majority of neurons in both wild-type and tipE mutant (tipE(-)) embryo cultures fire sodium-dependent action potentials in response to depolarizing current injection. However, the percentage of tipE- neurons capable of firing repetitively during a sustained depolarization is significantly reduced. Expression of a tipE(+) transgene, in tipE- neurons, restores repetitive firing to wild-type levels. Analysis of underlying currents reveals a slower rate of repolarization-dependent recovery of voltage-gated sodium currents during repeated activation in tipE- neurons. This phenotype is also rescued by expression of the tipE+ transgene. These data demonstrate that tipE regulates sodium-dependent repetitive firing and recovery of sodium currents during repeated activation. Furthermore, the duration of the interstimulus interval necessary to fire a second full-sized action potential is significantly longer in single- versus multiple-spiking transgenic neurons, suggesting that a slow rate of recovery of sodium currents contributes to the decrease in repetitive firing in tipE- neurons.