Tenidap Oppositely Regulates the Leak Conductance and Inwardly Rectifying K+ Channels of Striatal Projection Neurons in MiceAuthor(s): Tangna Sun, Bo Zhao, Junling Zhu, Jianhong Duan, Zhuyi Li, Wenting Wang
The imbalance between the direct and indirect pathways of the striatum is involved in psychiatric disorders such as autism. The inwardly rectifying K+ (Kir) channel could fine tune the balance between these two striatal pathways, which suggested that the pharmacological modulation of the Kir channel may be useful for research of striatal-related function and disease. The K+ leak channel is involved in determining resting membrane potential and excitability with Kir and also shares some common regulators with Kir channels. Tenidap is a class of anti-inflammatory drugs that was found to be a potential opener of the Kir channel and the modulator for other ion channels. It is unknown whether Tenidap could modulate both Kir and the K+ leak channel.
Methods and findings
In the present work, we tested the effect of tenidap on Kir and the leak current with whole-cell patch-clamp recording in acute brain slices in mice. We found that tenidap actually inhibited the Kir current but enhanced the leak current in MSNs in the striatum. SKF83822, a dopaminergic D1 receptor agonist, could increase the Kir current but did not affect the leak channels. In addition, it could increase Kir-mediated membrane resonant frequencies in MSNs. However, tenidap decreased the resonant frequency of MSNs, which also supported that tenidap did inhibit Kir in striatal MSNs in mice.
Our results demonstrated that tenidap oppositely regulates the Kir and leak currents, which also suggested that K+ leak channels should be taken into account when investigating the role of drugs that have multiple downstream targets, such as tenidap. These results suggested that tenidap may be used to differentiate the role of the Kir and leak channels in striatal-related functions and to provide a potential tool for interventions in striatal-related diseases.