Sodium Channel Mutations in Paramyotonia Congenita Exhibit Similar Biophysical Phenotypes In vitro

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 26; pp. 12785 - 12789
• Main Authors: Yang, Naibo, Ji, Sen, Zhou, Ming, Ptacek, Louis J., Barchi, Robert L., Horn, Richard, George, Alfred L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of the Sciences of the United States of America 20-12-1994; National Acad Sciences; National Academy of Sciences
• Subjects: Base Sequence; Biophysical Phenomena; Biophysics; Cell lines; Cellular biology; Depolarization; DNA Primers - chemistry; Electric Conductivity; Electric current; Electric potential; Genetic mutation; Humans; In Vitro Techniques; Kinetics; Medical research; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Myotonia - genetics; Myotonia - physiopathology; Paralyses, Familial Periodic - physiopathology; Phenotypes; Skeletal muscle; Skeletal system; Sodium; Sodium Channels - physiology; Structure-Activity Relationship; Temperature; Time constants
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.26.12785

Mutations in the skeletal muscle voltagegated Na+channel α-subunit have been found in patients with two distinct hereditary disorders of sarcolemmal excitation: hyperkalemic periodic paralysis (HYPP) and paramyotonia congenita (PC). Six of these mutations have been functionally expressed in a heterologous cell line (tsA201 cells) using the recombinant human skeletal muscle Na+channel α-subunit cDNA hSkM1. PC mutants from diverse locations in this subunit (T1313M, L1433R, R1448H, R1448C, A1156T) all exhibit a similar disturbance in channel inactivation characterized by reduced macroscopic rate, accelerated recovery, and altered voltage dependence. PC mutants had no significant abnormality in activation. In contrast, one HYPP mutation studied (T704M) has a normal inactivation rate but exhibits shifts in the midpoints of steady-state activation and inactivation along the voltage axis. These findings help to explain the phenotypic differences between HYPP and PC at the molecular and biophysical level and contribute to our understanding of Na+channel structure and function.