Genetic and epigenetic control of the Na-G ion channel expression in glia

The Na-G ion channel, previously cloned from a rat astroglia cDNA library, belongs to a new family of ion channels, related to but distinct from the predominant brain and muscle fast voltage-gated Na(+) channels. In vivo, the corresponding transcripts are widely expressed in peripheral nervous system neurons and glia, but only in selected subpopulations of neuronal and glia-like cells of the central nervous system. In the present report, we show that Na-G messenger RNA level in astrocyte and Schwann cell cultures is modulated in a cell-specific manner by several growth factors, hormones, and intracellular second messengers pathways. Striking changes in transcript level were observed in the two types of glia in response to protein-kinase A activation and to treatment with the neuregulin glial growth factor, indicating regulation of the Na-G gene by neuroglial signaling. By transient transfection of Na-G/reporter constructs into cultured cells, we show that a short genomic region, encompassing the first exon and 375 bp upstream, bears a high glial-specific transcriptional activity while part of the first intron behaves as a negative regulatory element. In vivo footprinting experiments revealed binding of glial-specific nuclear factors to several sites of the Na-G promoter region. Finally, Na-G/reporter constructs are shown to sustain a low but reproducible transcriptional response to cAMP, accounting in part for the elevation in mRNA level elicited by cAMP in Schwann cells and its reduction in astrocytes.