Contribution of sodium channel neuronal isoform Nav11 to late sodium current in ventricular myocytes from failing hearts
Recommended Citation
Mishra S, Reznikov V, Maltsev VA, Undrovinas NA, Sabbah HN, Undrovinas A. Contribution of sodium channel neuronal isoform Nav1.1 to late sodium current in ventricular myocytes from failing hearts. J Physiol. 2015 Mar 15;593(6):1409-27.
Document Type
Article
Publication Date
3-15-2015
Publication Title
The Journal of physiology
Abstract
KEY POINTS: 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.
ABSTRACT: 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.
Medical Subject Headings
Action Potentials; Animals; Calcium Signaling; Cells, Cultured; Dogs; Ethyl Methanesulfonate; Heart Failure; Heart Ventricles; Humans; Myocytes, Cardiac; NAV1.1 Voltage-Gated Sodium Channel; Protein Isoforms; Sodium Channel Blockers; Tetrodotoxin
PubMed ID
25772296
Volume
593
Issue
6
First Page
1409
Last Page
1427
