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J Biol Chem, Vol. 275, Issue 2, 1079-1088, January 14, 2000

Cloning, Localization, and Functional Expression of Sodium Channel 1A Subunits^*

Kristin A. Kazen-Gillespie, David S. Ragsdale^§, Michael R. D'Andrea^¶, Laura N. Mattei, Kathryn E. Rogers^¶, and Lori L. Isom

From the  Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109-0632, ^§ Montreal Neurological Institute, McGill University, Montreal, Quebec H3A2B4, Canada, and ^¶ The R. W. Johnson Pharmaceutical Research Institute, Springhouse, Pennsylvania 19477-0776

Auxiliary 1 subunits of voltage-gated sodium channels have been shown to be cell adhesion molecules of the Ig superfamily. Co-expression of  and 1 subunits modulates channel gating as well as plasma membrane expression levels. We have cloned, sequenced, and expressed a splice variant of 1, termed 1A, that results from an apparent intron retention event. 1 and 1A are structurally homologous proteins with type I membrane topology; however, they contain little to no amino acid homology beyond the shared Ig loop region. 1A mRNA expression is developmentally regulated in rat brain such that it is complementary to 1. 1A mRNA is expressed during embryonic development, and then its expression becomes undetectable after birth, concomitant with the onset of 1 expression. In contrast, 1A mRNA is expressed in adult adrenal gland and heart. Western blot analysis revealed 1A protein expression in heart, skeletal muscle, and adrenal gland but not in adult brain or spinal cord. Immunocytochemical analysis of 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 IIA and 1A subunits in Chinese hamster lung 1610 cells results in a 2.5-fold increase in sodium current density compared with cells expressing IIA alone. This increase in current density reflected two effects of 1A: 1) an increase in the proportion of cells expressing detectable sodium currents and 2) an increase in the level of functional sodium channels in expressing cells. [³H]Saxitoxin binding analysis revealed a 4-fold increase in B_max with no change in K_D in cells coexpressing IIA and 1A compared with cells expressing IIA alone. 1A-expressing cell lines also revealed subtle differences in sodium channel activation and inactivation. These effects of 1A subunits on sodium channel function may be physiologically important events in the development of excitable cells.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF182949.

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