No apparent requirement for neuronal sodium channels in excitation-contraction
coupling in rat ventricular myocytes.
Circ. Res., 98 (5):
667--674 (March 2006)DOI: 10.1161/01.RES.0000209963.02720.70
Abstract
The majority of Na channels in the heart are composed of the tetrodotoxin
(TTX)-resistant (KD, 2 to 6 micromol/L) "cardiac" NaV1.5 isoform;
however, TTX-sensitive (KD, 1 to 25 nmol/L) "neuronal" Na channel
isoforms have recently been detected in several cardiac preparations.
In the present study, we determined the functional subcellular localization
of Na channel isoforms (according to their TTX sensitivity) in rat
ventricular myocytes by recording INa in control and detubulated
myocytes. We found that TTX-sensitive INa (KD, &8.8 nmol/L) makes
up 14+/-3\% of total INa in control and < or =4\% in detubulated
myocytes and calculated that &80\% of TTX-sensitive INa is located
in the t-tubules, where it generates &1/3 of t-tubular INa. In contrast,
TTX-resistant INa is located predominantly (&78\%) at the surface
membrane. We also investigated the possible contribution of TTX-sensitive
INa to excitation-contraction coupling, using 200 nmol/L TTX to selectively
block TTX-sensitive INa. TTX decreased the rate of depolarization
of the action potential by 10\% but did not delay the rise of systolic
Ca$^2+$ in the center of the cell (transverse confocal line scan),
suggesting that TTX-sensitive INa does not play a role in synchronizing
Ca$^2+$ release at the t-tubules; the amplitude of the Ca$^2+$
transient and contraction were also unchanged by 200 nmol/L TTX.
The quantity of charge entering via ICa elicited by control or TTX
action potential waveforms was similar, suggesting that the trigger
for Ca$^2+$ release is not altered by blocking TTX-sensitive
INa. We conclude that neuronal INa is concentrated at the t-tubules,
but there is no evidence of a requirement for these channels in normal
excitation-contraction coupling in ventricular myocytes.
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