BNaC1 and BNaC2 constitute a new family of human neuronal sodium channels related to degenerins and epithelial sodium channels - PubMed (original) (raw)

Comparative Study

J García-Añoveros et al. Proc Natl Acad Sci U S A. 1997.

Abstract

The recently defined DEG/ENaC superfamily of sodium channels includes subunits of the amiloride-sensitive epithelial sodium channel (ENaC) of vertebrate colon, lung, kidney, and tongue, a molluscan FMRFamide-gated channel (FaNaC), and the nematode degenerins, which are suspected mechanosensory channels. We have identified two new members of this superfamily (BNaC1 and BNaC2) in a human brain cDNA library. Phylogenetic analysis indicates they are equally divergent from all other members of the DEG/ENaC superfamily and form a new branch or family. Human BNaC1 maps to 17q11.2-12 and hBNaC2 maps to 12q12. Northern blot and mouse brain in situ hybridizations indicate that both genes are coexpressed in most if not all brain neurons, although their patterns of expression vary slightly, and are expressed early in embryogenesis and throughout life. By analogy to the ENaCs and the degenerins, which form heteromultimeric channels, BNaC1 and BNaC2 may be subunits of the same channel.

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Figures

Figure 1

Figure 1

Phylogenetic and structural comparison of DEG/ENaC superfamily members. The conserved hydrophobic regions (63 amino acids) of all these proteins were aligned, and the tree was generated by parsimony analysis using the

paup

program.

Figure 2

Figure 2

Alignment of amino acid sequences predicted for human BNaC1 and BNaC2. Identical residues are shaded, hydrophobic regions are boxed, cysteines conserved in other DEG/ENaC proteins are circled, predicted _N_-glycosylation sites are indicated by asterisks, casein kinase II phosphorylation sites by solid squares, protein kinase sites by solid circles, and a cAMP- and cGMP-dependent protein kinase site by an open circle. The additional 46 amino acids predicted from one of the hBNaC2 cDNAs are indicated under the rest of the sequence. The amino acid sequence of hBNaC1 matches exactly that reported as mDEG (13), but differs from that reported as BNC1 (12), which contains an alanine rather than a threonine at position 495.

Figure 3

Figure 3

Northern blot hybridization of human (A, B, D, and E) and mouse (C and F) BNaC1 (A_–_C) and BNaC2 (D_–_F). The blots contain mRNA from various human organs (A and D), parts of the human brain (B and E), or mouse embryos at several stages (C and F). Control hybridization of human β-actin cDNA to each blot (not shown) gave bands of nearly identical intensities in every lane, indicating that the amount of total mRNA per lane is about the same.

Figure 4

Figure 4

In situ hybridization of mBNaC1 (A, E, and G) and mBNaC2 (B and C) riboprobes to mouse brain sagittal sections, and DAPI stain of nuclei in those same sections (D, F, and H). Glial cell nuclei are brighter. (A and B) Whole brain. (C and D) Portion of cerebellum with white matter, granule cell layer, Purkinje cell layer, and molecular layer indicated. (E and F) Portion of parietal cortex, corpus callosum, ependymal cell layer, and ventricular space. (G and H) Anterior commissure and surrounding neuronal areas. Hybridization of control sense riboprobes to adjacent sections under the same conditions gives no signal (not shown). In all pictures (except for C and D, whose orientation has not been determined), anterior is to the left and ventral is down.

Figure 5

Figure 5

Mapping of hBNaC1 (A_–_C) and hBNaC2 (D_–_F) genes. FISH of cDNA fragments to human chromosomes (A and D), DAPI staining of the same chromosomes (B and E), and distribution of labeled sites in idiograms (C and F). Each dot represents double fluorescent in situ hybridization signals detected on the chromosome.

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