Primary Structure and Functional Expression of the Human Cardiac Tetrodotoxin-Insensitive Voltage-Dependent Sodium Channel

• Published in: Proceedings of the National Academy of Sciences - PNAS 1992-01, Vol.89 (2), p.554-558
• Main Authors: Gellens, Mary E., George, Alfred L., Chen, Liqiong, Chahine, Mohamed, Horn, Richard, Barchi, Robert L., Kallen, Roland G.
• Format: Article
• Language: English
• Subjects: Adults; Amino Acid Sequence; Amino acids; Animals; Biological and medical sciences; Blotting, Northern; Cell physiology; Cloning, Molecular; Complementary DNA; DNA - genetics; Electric Conductivity; Electric potential; Fundamental and applied biological sciences. Psychology; Gene Expression; genes; Heart; Humans; Ion Channel Gating; Kinetics; Medical research; Membrane and intracellular transports; Membrane Potentials; Molecular and cellular biology; Molecular Sequence Data; Myocardium - chemistry; Oocytes; Protein isoforms; RNA; RNA, Messenger - genetics; Sequence Alignment; Skeletal muscle; Sodium - physiology; Sodium channels; Sodium Channels - physiology; tetrodotoxin; Tetrodotoxin - pharmacology; Xenopus laevis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.89.2.554

The principal voltage-sensitive sodium channel from human heart has been cloned, sequenced, and functionally expressed. The cDNA, designated hH1, encodes a 2016-amino acid protein that is homologous to other members of the sodium channel multigene family and bears >90% identity to the tetrodotoxin-insensitive sodium channel characteristic of rat heart and of immature and denervated rat skeletal muscle. Northern blot analysis demonstrates an ≈9.0-kilobase transcript expressed in human atrial and ventricular cardiac muscle but not in adult skeletal muscle, brain, myometrium, liver, or spleen. When expressed in Xenopus oocytes, hH1 exhibits rapid activation and inactivation kinetics similar to native cardiac sodium channels. The single channel conductance of hH1 to sodium ions is about twice that of the homologous rat channel and hH1 is more resistant to block by tetrodotoxin (IC50= 5.7 μM). hH1 is also resistant to μ-conotoxin but sensitive to block by therapeutic concentrations of lidocaine in a use-dependent manner.