title: Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels.
abstract: Long QT syndrome type 3 (LQT3) has been traced to mutations of the cardiac Na(+) channel (Na(v)1.5) that produce persistent Na(+) currents leading to delayed ventricular repolarization and torsades de pointes. We performed mutational analyses of patients suffering from LQTS and characterized the biophysical properties of the mutations that we uncovered. One LQT3 patient carried a mutation in the SCN5A gene in which the cysteine was substituted for a highly conserved tyrosine (Y1767C) located near the cytoplasmic entrance of the Na(v)1.5 channel pore. The wild-type and mutant channels were transiently expressed in tsA201 cells, and Na(+) currents were recorded using the patch-clamp technique. The Y1767C channel produced a persistent Na(+) current, more rapid inactivation, faster recovery from inactivation, and an increased window current. The persistent Na(+) current of the Y1767C channel was blocked by ranolazine but not by many class I antiarrhythmic drugs. The incomplete inactivation, along with the persistent activation of Na(+) channels caused by an overlap of voltage-dependent activation and inactivation, known as window currents, appeared to contribute to the LQTS phenotype in this patient. The blocking effect of ranolazine on the persistent Na(+) current suggested that ranolazine may be an effective therapeutic treatment for patients with this mutation. Our data also revealed the unique role for the Y1767 residue in inactivating and forming the intracellular pore of the Na(v)1.5 channel.
authors.affiliation: Centre de Recherche, Université Laval Robert-Giffard, Quebec City, Quebec, Canada.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.forename: Carlo
authors.initials: C
authors.lastname: Napolitano
authors.forename: Michael E
authors.initials: ME
authors.lastname: O'Leary
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chahine
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000293:Adolescent; D004252:DNA Mutational Analysis; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics*; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010879:Piperazines; C568320:SCN5A protein, human; D015222:Sodium Channels; D000069458:Ranolazine