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 μM 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 μM 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 21 interact directly with Na⁺ channels, perhaps at a fatty acid binding domain, by decreasing the total gating charge and altering fast-inactivation kinetics.