Cloning, localization, and functional expression of sodium channel beta 1Asubunits

Auxiliary beta 1 subunits of voltage-gated sodium channels have been shown to be cell adhesion molecules of the Ig superfamily, Co-expression of alpha and beta 1 subunits modulates channel gating as well as plasma membrane ex pression levels. We have cloned, sequenced, and expressed a splice variant of beta 1, termed beta 1A, that results from an apparent intron retention e vent. beta 1 and beta 1A are structurally homologous proteins with type I m embrane topology; however, they contain little to no amino acid homology be yond the shared Ig loop region. beta 1A mRNA expression is developmentally regulated in rat brain such that it is complementary to beta 1. beta 1A mRN A is expressed during embryonic development, and then its expression become s undetectable after birth, concomitant with the onset of beta 1 expression , In contrast, beta 1A mRNA is expressed in adult adrenal gland and heart. Western blot analysis revealed beta 1A protein expression in heart, skeleta l muscle, and adrenal gland but not in adult brain or spinal cord. Immunocy tochemical analysis of beta 1A expression revealed selective expression in brain and spinal cord neurons, with high expression in heart and all dorsal root ganglia neurons. Co-expression of alpha IIA and beta 1A subunits in C hinese hamster lung 1610 cells results in a 2.5-fold increase in sodium cur rent density compared with cells expressing alpha IIA alone. This increase in current density reflected two effects of beta 1A: 1) an increase in the proportion of cells expressing detectable sodium currents and 2) an increas e in the level of functional sodium channels in expressing cells. [H-3]Saxi toxin binding analysis revealed a 4-fold increase in B-max with no change i n K-D in cells coexpressing alpha IIA and beta 1A compared with cells expre ssing alpha IIA alone. beta 1A-expressing cell lines also revealed subtle d ifferences in sodium channel activation and inactivation. These effects of beta 1A subunits on sodium channel function may be physiologically importan t events in the development of excitable cells.