NCX1 is a new rest target gene: role in cerebral ischemia

The Na(+)-Ca(2+) exchanger 1 (NCX1), a bidirectional transporter that mediatesthe electrogenic exchange of one calcium ion for three sodium ions across theplasmamembrane, is known to be involved in brain ischemia. Since theRE1-silencing transcription factor (REST) is a key modulator of neuronal geneexpression in several neurological conditions, we studied the possibleinvolvement of REST in regulating NCX1 gene expression and activity in stroke. Wefound that: (1) REST binds in a sequence specific manner and represses through H4deacetylation, ncx1 gene in neuronal cells by recruting CoREST, but not mSin3A.(2)In neurons and in SH-SY5Y cells REST silencing by siRNA and site-directmutagenesis of REST consensus sequence on NCX1 brain promoter determined anincrease in NCX1 promoter activity. (3)By contrast, REST overexpression caused a reduction in NCX1 protein expression and activity. (4)Interestingly, in ratssubjected to transient middle cerebral artery occlusion (tMCAO) and inorganotypic hippocampal slices or SH-SY5Y cells exposed to oxygen and glucosedeprivation (OGD) plus reoxygenation (RX), the increase in REST was associatedwith a decrease in NCX1. However, this reduction was reverted by REST silencing. (5)REST knocking down, along with the deriving NCX1overexpression in the deep Vand VIb cortical layers caused a marked reduction in infarct volume after tMCAO. Double silencing of REST and NCX1 completely abolished neuroprotection induced bysiREST administration. Collectively, these results demonstrate that REST, byregulating NCX1 expression, may represent a potential druggable target for thetreatment of brain ischemia.