title: Contribution of sodium channel neuronal isoform Nav1.1 to late sodium current in ventricular myocytes from failing hearts.
abstract: CONCLUSIONS
  Late Na(+) current (INaL) contributes to action potential remodelling and Ca(2+)/Na(+) changes in heart failure. The molecular identity of INaL remains unclear. The contributions of different Na(+) channel isoforms, apart from the cardiac isoform, remain unknown. We discovered and characterized a substantial contribution of neuronal isoform Nav1.1 to INaL. This new component is physiologically relevant to the control of action potential shape and duration, as well as to cell Ca(2+) dynamics, especially in heart failure.
  Late Na(+) current (INaL) contributes to action potential (AP) duration and Ca(2+) handling in cardiac cells. Augmented INaL was implicated in delayed repolarization and impaired Ca(2+) handling in heart failure (HF). We tested if Na(+) channel (Nav) neuronal isoforms contribute to INaL and Ca(2+) cycling defects in HF in 17 dogs in which HF was achieved via sequential coronary artery embolizations. Six normal dogs served as control. Transient Na(+) current (INaT ) and INaL in left ventricular cardiomyocytes (VCMs) were recorded by patch clamp while Ca(2+) dynamics was monitored using Fluo-4. Virally delivered short interfering RNA (siRNA) ensured Nav1.1 and Nav1.5 post-transcriptional silencing. The expression of six Navs was observed in failing VCMs as follows: Nav1.5 (57.3%) > Nav1.2 (15.3%) > Nav1.1 (11.6%) > Nav2.1 (10.7%) > Nav1.3 (4.6%) > Nav1.6 (0.5%). Failing VCMs showed up-regulation of Nav1.1 expression, but reduction of Nav1.6 mRNA. A similar Nav expression pattern was found in samples from human hearts with ischaemic HF. VCMs with silenced Nav1.5 exhibited residual INaT and INaL (∼30% of control) with rightwardly shifted steady-state activation and inactivation. These currents were tetrodotoxin sensitive but resistant to MTSEA, a specific Nav1.5 blocker. The amplitude of the tetrodotoxin-sensitive INaL was 0.1709 ± 0.0299 pA pF(-1) (n = 7 cells) and the decay time constant was τ = 790 ± 76 ms (n = 5). This INaL component was lacking in VCMs with a silenced Nav1.1 gene, indicating that, among neuronal isoforms, Nav1.1 provides the largest contribution to INaL. At -10 mV this contribution is ∼60% of total INaL. Our further experimental and in silico examinations showed that this new Nav1.1 INaL component contributes to Ca(2+) accumulation in failing VCMs and modulates AP shape and duration. In conclusion, we have discovered an Nav1.1-originated INaL component in dog heart ventricular cells. This component is physiologically relevant to controlling AP shape and duration, as well as to cell Ca(2+) dynamics.
authors.affiliation: Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Sudhish
authors.initials: S
authors.lastname: Mishra
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Reznikov
authors.forename: Victor A
authors.initials: VA
authors.lastname: Maltsev
authors.forename: Nidas A
authors.initials: NA
authors.lastname: Undrovinas
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.forename: Albertas
authors.initials: A
authors.lastname: Undrovinas
mesh_terms: D000200:Action Potentials; D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D004285:Dogs; D005020:Ethyl Methanesulfonate / Q000031:analogs & derivatives / Q000494:pharmacology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D020033:Protein Isoforms; D026941:Sodium Channel Blockers; C093171:methanethiosulfonate ethylammonium; D013779:Tetrodotoxin; D005020:Ethyl Methanesulfonate