Mechanism of modulation of the voltage-gated skeletal and cardiac muscle sodium channels by fatty acids.
Voltage-gated rat skeletal muscle and cardiac Na+ channels are modulated by exogenous unsaturated fatty acids. Application of 1-10 microM arachidonic or oleic acids reversibly depressed Na+ channel conductance and shifted the inactivation curve to hyperpolarizing potentials. These effects were not prevented by inhibitors of lipoxygenase, cyclooxygenase, cytochrome P-450 epoxygenase, or protein kinase C. Neither palmitic acid nor methyl ester oleate had an effect on the inward Na+ current, suggesting that trivial variations in membrane fluidity are not responsible for the Na+ current depression or kinetic changes. Arachidonic acid altered fast Na+ inactivation without changing the slow inactivation kinetics. Moreover, skeletal muscle Na+ channel gating currents were markedly decreased by 2 microM arachidonic acid. Finally, nonstationary noise analysis indicated that both the number of channels and the open probability were slightly decreased without change in the single-channel conductance. These data suggest that unsaturated fatty acids such as arachidonic and oleic acids 1) specifically regulate voltage-gated Na+ channels and 2) interact directly with Na+ channels, perhaps at a fatty acid binding domain, by decreasing the total gating charge and altering fast-inactivation kinetics.
Bendahhou
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Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Cummins
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TR
Agnew
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D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D004594:Electrophysiology; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating; D007536:Isomerism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D019301:Oleic Acid / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism*; D014162:Transfection
D005227:Fatty Acids; D015222:Sodium Channels; D016718:Arachidonic Acid; D019301:Oleic Acid; D011493:Protein Kinase C