A cDNA library derived from human cerebral cortex was screened for the presence of sodium channel a subunit-specific clones. Ligton of three overlapping clones generated a full-length cDNA clone, HBA, that provided the complete nucleotide sequence coding for a protein of 2005 amino acids. The predicted structure suggests four homologous repeats and exhibits greatest homology and structural similarity to the rat brain sodium channel H. A second cDNA clone, HBB, that encodes a different subtype of sodium channel was isolated. Hybridization of DNA a nts from the 3' untranslated region of HBA and PCR with primers derived from HBB with human-hamster somatic cell hybrids loalie these clones to human chromosome 2. In situ hybridization to human metaphase chromosomes mapped the structural genes for both HBA and HBB sodium channels to chromosome 2q23-24.3. The sodium channe HBA gene product was expressed by transection in CHO cells. Expressed HBA currents were voltage-dependent, sodium-selective, and tetrodotoxinsensitive and, thus, exhibit the biophysical and pharmacological properties characteristic of sodium channels.Signaling in the brain is mediated by the activity of voltagegated and ligand-gated ion channels. Sodium channels, archetypes of the multimember family of voltage-gated channels, are responsible for the rising phase of action potentials in electrically excitable cells (1) and have been extensively studied in a variety of cells, including human neurons (1, 2). Sodium channels vary in subunit composition and complexity (1,3,4). In rat brain, the channel complex consists of an a subunit ofMr -260,000 and two nonidentical p subunits ofMr -39,000 and 37,000 (3, 4). The a subunit is sufficient to form a functional channel, as demonstrated by heterologous expression of cDNAs (3-6); the role of the smaller subunits is not yet understood.Sodium channels are the targets of a variety of clinically valuable drugs, such as local anesthetics, anticonvulsants, or antiarrhythmics, and of various toxins (1, 4). However, little is known about the molecular structure and specific pharmacology of human brain channels, goals hitherto hampered by the limited accessibility of the tissue to experimental manipulation. Availability of cDNA clones for these proteins and their expression in heterologous systems would provide powerful tools to investigate their fundamental structure and pharmacological properties and to assess efficacy of therapeutic intervention. Localization of sodium channel genes to human chromosomes is an important step in exploring their involvement in the etiology of heritable neuropsychiatric disorders that have been mapped and in developing molecular markers for clinical screening programs (7).We report here the complete amino acid sequence of the a subunit of a human brain sodium channel,1 its localization to human chromosome 2q23-24.3, and its expression from cDNA in CHO cells. A preliminary account ofthis report was presented elsewhere (8). MATERIALS AND METHODSIsolion of cDNA Clones. Standard mol...