title: A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation-contraction coupling in the mouse heart.
abstract: Evidence supports the expression of brain-type sodium channels in the heart. Their functional role, however, remains controversial. We used global Na(V)1.6-null mice to test the hypothesis that Na(V)1.6 contributes to the maintenance of propagation in the myocardium and to excitation-contraction (EC) coupling. We demonstrated expression of transcripts encoding full-length Na(V)1.6 in isolated ventricular myocytes and confirmed the striated pattern of Na(V)1.6 fluorescence in myocytes. On the ECG, the PR and QRS intervals were prolonged in the null mice, and the Ca(2+) transients were longer in the null cells. Under patch clamping, at holding potential (HP) = -120 mV, the peak I(Na) was similar in both phenotypes. However, at HP = -70 mV, the peak I(Na) was smaller in the nulls. In optical mapping, at 4 mM [K(+)](o), 17 null hearts showed slight (7%) reduction of ventricular conduction velocity (CV) compared to 16 wild-type hearts. At 12 mM [K(+)](o), CV was 25% slower in a subset of 9 null vs. 9 wild-type hearts. These results highlight the importance of neuronal sodium channels in the heart, whereby Na(V)1.6 participates in EC coupling, and represents an intrinsic depolarizing reserve that contributes to excitation.
authors.affiliation: Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48108, USA.
authors.forename: Sami F
authors.initials: SF
authors.lastname: Noujaim
authors.forename: Kuljeet
authors.initials: K
authors.lastname: Kaur
authors.forename: Michelle
authors.initials: M
authors.lastname: Milstein
authors.forename: Julie M
authors.initials: JM
authors.lastname: Jones
authors.forename: Philip
authors.initials: P
authors.lastname: Furspan
authors.forename: Daniel
authors.initials: D
authors.lastname: Jiang
authors.forename: David S
authors.initials: DS
authors.lastname: Auerbach
authors.forename: Todd
authors.initials: T
authors.lastname: Herron
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D004562:Electrocardiography; D005110:Extracellular Space / Q000378:metabolism; D006329:Heart Conduction System / Q000503:physiopathology*; D006947:Hyperkalemia / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C491046:Scn8a protein, mouse; D015222:Sodium Channels; D011188:Potassium; D002118:Calcium