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

Abstract

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. GLIA 33:230–240, 2001. © 2001 Wiley‐Liss, Inc.

Induction of sodium channel Nax (SCN7A) expression in rat and human hippocampus in temporal lobe epilepsy

“…In adult rat and human hippocampus, the expression in glial cells was detected only in epileptic tissue and, as confirmed by double‐labeling experiments, was confined to reactive astrocytes. Induction of Na x in reactive glia following excitotoxic neuronal injury has been previously suggested (Gautron et al., 2001). Herein we confirm this possibility showing that induction in reactive astrocytes can be triggered by an epileptogenic brain insult.…”

“…The process of astroglial reactivity has also been shown to be associated with reversion to an immature cell state and expression of early developmental genes (Ridet et al., 1997). The Na x has been originally suggested to be a glial sodium channel (Gautron et al., 1992); however, (except for the specialized glia‐like cells in the CVOs), the protein is undetectable in resting astroglia and oligodendrocytes in normal brain (Gautron et al., 1992, 2001). In adult rat and human hippocampus, the expression in glial cells was detected only in epileptic tissue and, as confirmed by double‐labeling experiments, was confined to reactive astrocytes.…”

“…However, recent experimental data, using Na x knockout mice, indicate that the channel serves as a sodium‐level sensor of the body fluid (Hiyama et al., 2002; Watanabe et al., 2003; Shimizu et al., 2007). This channel was originally thought to be a glial sodium channel (Na‐G) (Gautron et al., 1992, 2001; Black et al., 1994). However, in situ hybridization studies revealed that SCN7A mRNA is also expressed in neuronal cells in the peripheral nervous system (PNS), as well as in central nervous system (CNS), where it is expressed in restricted neuronal subpopulations such as thalamus, hippocampus, cerebellum, and median preoptic nucleus (Gautron et al., 1992; Black et al., 1996; Felts et al., 1997; Grob et al., 2004; Fukuoka et al., 2008).…”