Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. In the present study, we find that the global Slack KO male mice exhibit anxious behaviors, whereas the Slack Y777H male mice manifest anxiolytic behaviors. The expression of Slack channels is rich in basolateral amygdala (BLA) glutamatergic neurons and downregulated in chronic corticosterone-treated mice. In addition, electrophysiological data show enhanced excitability of BLA glutamatergic neurons in the Slack KO mice and decreased excitability of these neurons in the Slack Y777H mice. Furthermore, the Slack channel deletion in BLA glutamatergic neurons is sufficient to result in enhanced avoidance behaviors, whereas Kcnt1 gene expression in the BLA or BLA-ventral hippocampus (vHPC) glutamatergic projections reverses anxious behaviors of the Slack KO mice. Our study identifies the role of the Slack channel in controlling anxious behaviors by decreasing the excitability of BLA-vHPC glutamatergic projections, providing a potential target for anxiolytic therapies.

been fully understood. Using a combination of time-lapse confocal microscopy and patch-clamp techniques we investigated the time-dependent changes in the subcellular localization and channel activity of cardiac KCNQ1/KCNE1 in response to the prolonged calcium dependent protein kinase C (cPKC) activation. Plasma membrane localization of KCNQ1/KCNE1 was reduced after 30-min cPKC activation, accompanied by decrease in channel conductance. In addition, after the cPKC activation, KCNQ1/KCNE1 channel showed co-localization with the early-endosome marker Rab5. Dephospho-memetric mutation of a putative phosphorylation site in KCEN1 (S102) abolished the channel internalization and current inhibition. Internalization was also inhibited by cPKC-specific inhibitors or co-expression of dominant negative dynamin (DYN-K44A). Finally, inhibition of Rab5 prenylation by statins prevented cPKC-mediated channel internalization. Manipulations that inhibit channel internalization did not affect channel function in the absence of cPKC stimulation. In summary, our results show that Dyn and Rab5 GTPases are key regulators for cell surface expression and internalization of KCNQ1/KCNE1 channels to early endosomes under the chronic cPKC activation. Our findings also indicate that statin treatment may prevent cardiac electrophysiological remodeling under the pathophysiological condition by upregulating the expression levels of KCNQ1/KCNE1 at the plasma membrane in the cardiomyocytes.