Referenced in: none

Automatically associated channels: Nav1.5

Title: Molecular identity of the late sodium current in adult dog cardiomyocytes identified by Nav1.5 antisense inhibition.

Authors: Victor A Maltsev, John W Kyle, Sudhish Mishra, Abertas Undrovinas

Journal, date & volume: Am. J. Physiol. Heart Circ. Physiol., 2008 Aug , 295, H667-76

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18552167

Abstract
Late Na(+) current (I(NaL)) is a major component of the action potential plateau in human and canine myocardium. Since I(NaL) is increased in heart failure and ischemia, it represents a novel potential target for cardioprotection. However, the molecular identity of I(NaL) remains unclear. We tested the hypothesis that the cardiac Na(+) channel isoform (Na(v)1.5) is a major contributor to I(NaL) in adult dog ventricular cardiomyocytes (VCs). Cultured VCs were exposed to an antisense morpholino-based oligonucleotide (Na(v)1.5 asOligo) targeting the region around the start codon of Na(v)1.5 mRNA or a control nonsense oligonucleotide (nsOligo). Densities of both transient Na(+) current (I(NaT)) and I(NaL) (both in pA/pF) were monitored by whole cell patch clamp. In HEK293 cells expressing Na(v)1.5 or Na(v)1.2, Na(v)1.5 asOligo specifically silenced functional expression of Na(v)1.5 (up to 60% of the initial I(NaT)) but not Na(v)1.2. In both nsOligo-treated controls and untreated VCs, I(NaT) and I(NaL) remained unchanged for up to 5 days. However, both I(NaT) and I(NaL) decreased exponentially with similar time courses (tau = 46 and 56 h, respectively) after VCs were treated with Na(v)1.5 asOligo without changes in 1) decay kinetics, 2) steady-state activation and inactivation, and 3) the ratio of I(NaL) to I(NaT). Four days after exposure to Na(v)1.5 asOligo, I(NaT) and I(NaL) amounted to 68 +/- 6% (mean +/- SE; n = 20, P < 0.01) and 60 +/- 7% (n = 11, P < 0.018) of those in VCs treated by nsOligo, respectively. We conclude that in adult dog heart Na(v)1.5 sodium channels have a "functional half-life" of approximately 35 h (0.69tau) and make a major contribution to I(NaL).