Na channel subunits are structurally homologous to cell adhesion molecules

ß1, ß1A, ß2 and ß3 are transmembrane proteins with type I topology: containing an extracellular N-terminus, a single transmembrane segment, and an intracellular C-terminus. ß1 and ß1A are splice variants of the SCN1B gene (Kazen-Gillespie et al 2000). ß3 is closely related to ß1 and is the product of a separate gene, SCN3B (Morgan et al 2000). The expression of SCN1B and SCN3B mRNA is developmentally and anatomically regulated. In situ hybridization studies comparing ß1 and ß3 localization in the adult CNS suggested that the expression of these two subunits is complementary (Morgan et al 2000). The developmental expression patterns of ß1 and ß1A RNA showed that ß1A is expressed early in embryonic brain development while ß1 is not (Kazen-Gillespie et al 2000). ß1A expression decreases after birth, concomitant with the emergence of ß1 expression. In the adult rat, immunolocalization studies showed ß1A protein expression in heart and dorsal root ganglion neurons with limited expression in brain (Kazen-Gillespie et al 2000).

All four ß subunit molecules contain extracellular immunoglobulin (Ig) domains that are structurally homologous to the V-set of the Ig superfamily that includes CAMs (Isom & Catterall 1996). This unique property of the Na+ channel auxiliary subunits was first discovered following sequence analysis of ß2, revealing that its extracellular domain contained an Ig fold and an extended region with similarity to the CAM contactin (Isom et al 1995a). Two distinct regions of the extracellular domain of contactin have greater than 40% amino acid sequence identity with Na+ channel ß2 subunits. Subsequent analysis of the extracellular domains of ß1/ß1A and ß3 showed a similar homology to the CAM myelin Po (McCormick et al 1998, Morgan et al 2000). Investigation of the amino acid sequences of ß1, ß1A, ß2 and ß3 shows that these proteins are closely related (Isom 2001). The Ig loop region (Isom et al 1994) of all four proteins is well conserved. While ß3 is most closely related to ß1, there are a number of conserved residues between ß3 and ß2 as well.

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