The balance between the formation of mixed protein-glutathione disulfides verses protein-protein disulfides depends on two factors: the relative redox potentials between cysteine thiols and GSH and the relative concentrations of reactant and product species. Previous findings have suggested that Kv4 channels, unlike Kv1.4 channels, do not produce redox-sensitive A-type K + currents. The A-type currents generated in oocytes by heterologous expression of Kv4 mRNA alone or poly-A mRNA from rat thalamus are insensitive to H2O2. Moreover, in hippocampal pyramidal neurons, the somatodendritic subthreshold A-type current mediated by Kv4 channels is also reportedly insensitive to oxidants. However, recent progress in our molecular understanding of the ISA channel complex challenges this overly simplistic conclusion. In addition to Kv4 pore-forming subunits, ISA channels contain notably two types of auxiliary subunits, the Kv channel-interacting proteins and dipeptidyl peptidase-like proteins. KChIP binding sequesters the Kv4 N-termini and effectively removes Ntype inactivation mediated by Kv4 subunits, meaning that in many neurons, ISA does not utilize N-type mechanisms. However, specific neuronal populations express two DPLP Nterminal variants that can independently confer N-type inactivation on the Kv4-KChIP-DPLP channel complex. The published literature has established that, unlike Kv1.4, the endogenous N-terminus of Kv4.2 produces fast inactivation that is insensitive to redox. Consequently, redox-sensitive A-type currents in neurons is thought to be likely expressed by Kv1.4 rather than Kv4 channels. Our heterologous expression studies strongly suggest that such interpretation should be reconsidered, since the Kv4-based subthreshold A-type current in neurons expressing DPP6a or DPP10a is likely also redox sensitive. Moreover, with a mixture of DPLPs being expressed in different neurons with different redox sensitivities, our results point to the importance of knowing the precise subunit SKF-86002 composition in order to predict the functional and regulatory properties of the native current. Furthermore, since DPP6a-conferred N-type inactivation of Kv4 channels is regulated via S-glutathionylation, follow-up studies to examine redox regulation of ISA in neurons or Kv4.2+KChIP3a+DPP6a currents in cultured mammalian cells must maintain normal intracellular GSH concentration to permit S-glutathionylation. This is an important consideration since, in the whole-cell patch configuration, the intracellular solutions dialyses out the intracellular milieu, and without GSH supplementation. Finally, our results emphasize the potential link between ISA, ROS, and oxidative stress-related disorders and the need for further studies. In neurons, ROS is robustly produced as a byproduct of normal aerobic metabolism and carefully kept in check by antioxidants such as GSH. At physiological concentration, ROS contributes to the induction and long-term potentiation,SMER 28 synaptic plasticity, learning and memory, and normal cognitive functions. Because ISA is also a major contributor to many of the same neurological phenomena modulated by ROS, our results would suggest that ROS may perform its function through reversible oxidation-reduction of DPP6a and DPP10a ISA auxiliary subunits. Under pathological conditions, an excessive accumulation of ROS results in neuronal oxidative stress, leading to apoptosis and reduced cognitive functions. An intriguing association between ROS and ISA has been reported in cerebellar granule cells where DPP6a is highly expressed. Exposure of CG cells to low external potassium concentrations leads to increased ROS levels, decreased cell viability, increased ISA amplitude, and slowing of inactivation kinetics. High-mobility group proteins are small DNA-binding proteins that serve an important role in transcriptional regulation.