title: Identification of Navβ1 residues involved in the modulation of the sodium channel Nav1.4.
abstract: Voltage-gated sodium channels (VGSCs) are heteromeric protein complexes that initiate action potentials in excitable cells. The voltage-gated sodium channel accessory subunit, Navβ1, allosterically modulates the α subunit pore structure upon binding. To date, the molecular determinants of the interface remain unknown. We made use of sequence, knowledge and structure-based methods to identify residues critical to the association of the α and β1 Nav1.4 subunits. The Navβ1 point mutant C43A disrupted the modulation of voltage dependence of activation and inactivation and delayed the peak current decay, the recovery from inactivation, and induced a use-dependent decay upon depolarisation at 1 Hz. The Navβ1 mutant R89A selectively delayed channel inactivation and recovery from inactivation and had no effect on voltage dependence or repetitive depolarisations. Navβ1 mutants Y32A and G33M selectively modified the half voltage of inactivation without altering the kinetics. Despite low sequence identity, highly conserved structural elements were identified. Our models were consistent with published data and may help relate pathologies associated with VGSCs to the Navβ1 subunit.
authors.affiliation: Laboratorio de Biofísica, Instituto de Fisiología, Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: Angel A
authors.initials: AA
authors.lastname: Islas
authors.affiliation: Laboratorio de Biofísica, Instituto de Fisiología, Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Sánchez-Solano
authors.affiliation: Facultad de Ciencias Químicas, Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: Thomas
authors.initials: T
authors.lastname: Scior
authors.affiliation: Centro de Química, Instituto de Ciencias, Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Millan-PerezPeña
authors.affiliation: Laboratorio de Biofísica, Instituto de Fisiología, Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Salinas-Stefanon
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D005260:Female; D015640:Ion Channel Gating / Q000502:physiology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011487:Protein Conformation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D021122:Protein Subunits; D015222:Sodium Channels