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1-subunit modifies the
kinetics and fatty acid block of hH1
Na+
channels
1 Charles A. Dana Research Institute and Harvard-Thorndike Laboratory, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, 2 Department of Medicine, Massachusetts General Hospital, and 3 Department of Anesthesia, Brigham and Women's Hospital, 4 Harvard Medical School, Boston, Massachusetts 02215; and 5 Department of Biological Sciences, Murray State University, Murray, Kentucky 42071
Voltage-gated cardiac Na+ channels are composed of
- and
1-subunits. In this study
1-subunit was cotransfected with the
-subunit of the
human cardiac Na+ channel (hH1
) in human
embryonic kidney (HEK293t) cells. The effects of this coexpression on
the kinetics and fatty acid-induced suppression of Na+
currents were assessed. Current density was significantly greater in
HEK293t cells coexpressing
- and
1-subunits
(INa,
) than in HEK293t cells expressing
-subunit alone (INa,
). Compared with
INa,
, the voltage-dependent inactivation and activation of INa,
were significantly
shifted in the depolarizing direction. In addition, coexpression with
1-subunit prolonged the duration of recovery from
inactivation. Eicosapentaenoic acid [EPA, C20:5(n-3)]
significantly reduced INa,
in a
concentration-dependent manner and at 5 µM shifted the midpoint voltage of the steady-state inactivation by
22 ± 1 mV. EPA also significantly accelerated channel transition from the resting state to
the inactivated state and prolonged the recovery time from
inactivation. Docosahexaenoic acid [C22:6(n-3)],
-linolenic acid [C18:3(n-3)], and conjugated linoleic acid
[C18:2(n-6)] at 5 µM significantly inhibited both
INa,
and INa,
. In contrast, saturated and monounsaturated fatty acids had no effects
on INa,
. This finding differs from the
results for INa,
, which was significantly
inhibited by both saturated and unsaturated fatty acids. Our data
demonstrate that functional association of
1-subunit
with hH1
modifies the kinetics and fatty acid block of
the Na+ channel.
-subunit; cardiac sodium ion channel; polyunsaturated fatty
acids
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