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Modulation of Human Muscle Sodium Channels by Intracellular Fatty Acids Is Dependent on the Channel Isoform
Free fatty acids (FFAs), including arachidonic acid (AA), are implicated in the direct and indirect modulation of a spectrum of voltage-gated ion channels. Skeletal muscle sodium channels can be either activated or inhibited by FFA exposure; the response is dependent on both FFA structure and site o...
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Published in: | The Journal of biological chemistry 1996-08, Vol.271 (32), p.19037-19041 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Free fatty acids (FFAs), including arachidonic acid (AA), are implicated in the direct and indirect modulation of a spectrum
of voltage-gated ion channels. Skeletal muscle sodium channels can be either activated or inhibited by FFA exposure; the response
is dependent on both FFA structure and site of exposure. Recombinant human skeletal muscle sodium channels (hSkM1) were transfected
into heterologous human renal epithelium HEK293t cells. Cytoplasmic delivery of 5 μ M AA augmented the voltage-activated sodium current of hSkM1 channels by 190% (±54 S.E., n = 7) over a 20-min period. Similar results were seen with 5 μ M oleic acid. Sodium currents in HEK293t cells transfected with human cardiac muscle sodium channels (hH1) were insensitive
to AA treatment, and exposure to oleic acid inhibited the hH1 currents over a 20-min period by 29% (±13 S.E., n = 5). The increase in hSkM1 current was not accompanied by shifts in voltage dependence of activation, steady-state inactivation,
or markedly altered kinetics of inactivation of the macroscopic current. The FFA-induced increase in sodium currents was not
dependent on protein kinase C activity. In contrast, both isoforms were reversibly inhibited by external application of unsaturated
FFA. Thus, the differential effects of FFA on skeletal muscle sodium channels first noted in cultured muscle cells can be
reproduced by expressing recombinant sodium channels in epithelial cells. Although the responses to applied FFAs could be
direct or indirect, we suggest that: 1) SkM1 has two classes of response to FFA, one which produces augmentation of macroscopic
currents with intracellular FFA, and a second which produces inhibition with extracellular FFA; 2) H1 has only one class of
response, which produces inhibition with extracellular FFA. A testable hypothesis is that the presence or absence of each
response is due to a specific structure in SkM1 or H1. These specific structures may directly interact with FFA or may interact
with intermediate components. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.271.32.19037 |