Global Ischemia Upregulates KCNQ1 Potassium Channel Activity in Neurons

Abstract

Transient forebrain or global ischemia induces delayed cell death of hippocampal CA1 pyramidal neurons and impaired cognition. Potassium (K+) channels are implicated as key players in ischemia-induced death. The KCNQ1 K+ channel assembles with the auxiliary subunit KCNE1 to produce the slow component of Ik in the heart. Emerging evidence indicates that KCNQ1 mRNA and protein are expressed not only in heart, but also brain, although its function in neurons is, as yet, unclear.The transcription factor REST (repressor element-1 silencing transcription factor)/NRSF (neuron-specific silencing factor) is upregulated in response to global ischemia and contributes to neuronal death. We recently showed that REST is enriched at the promoter of the KCNQ1 K+ channel in postischemic CA1, assessed by targeted ChIP-chip. Here we set out to assess a possible role for KCNQ1 in ischemia-induced neuronal death. Global ischemia in vivo elicited an increase in KCNQ1 mRNA at 24 (∼1.4 fold) and 48 h (∼3.5-fold; p < 0.04), as assessed by qPCR. Moreover, ischemia induced an increase in KCNQ1 protein at 24 (∼1.4 fold) and 48 h (∼1.6 fold; p < 0.004), as assessed by Western analysis. To examine KCNQ1 function in brain, we identified and recorded K+ currents from cultured hippocampal neurons with the specific KCNQ1 inhibitor Chromanol 293B (IC50=62μM) and confirmed them with a dominant-negative KCNQ1 mutant S277L which reduced the endogenous current by ∼50% (p < 0.005). Cultures exposed to oxygen-glucose deprivation (an in vitro model of ischemia) showed a marked increase in KCNQ1 currents at 48 h post ischemia (∼28%, p < 0.03). These results document the presence of functional KCNQ1 channels in hippocampal neurons, and their upregulation in response to ischemia, consistent with a possible contribution to delayed neuronal death of the CA1.