Emerging Role for KCNQ1 in Ischemia-Induced Neuronal Death

Abstract

The slowly activating component of the delayed rectifier potassium current, IKs, composed of KCNQ1-KCNE1 channel subunits, is an important contributor to normal cardiac repolarization. Emerging evidence indicates that KCNQ1 subunits are also expressed in brain, but its precise physiological role in neuronal function has not been investigated. Potassium channels are key players in ischemia-induced death of hippocampal CA1 pyramidal neurons which, in turn, leads to impaired cognition. REST, a gene silencing transcription factor, is up-regulated in global ischemia and contributes to neuronal death. Recently we showed that REST is enriched at the promoter of the KCNQ1 channel and that KCNQ1 mRNA and protein expression are increased in post-ischemic CA1 neurons. Additionally, functional KCNQ1 channels were identified in cultured neurons using KCNQ1-specific inhibitors Chromanol 293B and JNJ-303 and induction of oxygen-glucose deprivation (OGD) induced a marked increase in KCNQ1 currents (∼34%, p > 0.02), evident at 48 h post-ischemia. To assess a possible role for KCNQ1 in ischemia-induced neuronal death, we induced OGD in dissociated hippocampal neurons in the absence and presence of Chromanol 293B (100 µM) and treated with propidium iodine. Inhibition of KCNQ1 markedly diminished cell death, assessed at 24 h (21%, p > 0.002) and 48 h (28%, p > 0.001) suggesting that an up-regulation of KCNQ1 channels may contribute to ischemia-induced neuronal death. To examine a possible role for REST in ischemia-induced up-regulation of KCNQ1, we performed single-locus ChIP which revealed enrichment for REST by ∼2-fold and a decrease in trimethylation of lysine 27 on histone 3 (H3K27me3), an epigenetic mark of gene repression at the KCNQ1 promoter, consistent with the increase in KCNQ1 expression after ischemia. Our findings reveal, for the first time, a role for REST in KCNQ1 expression in response to ischemic insults.