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 modulat ed by exogenous unsaturated fatty acids. Application of 1-10 mu M arac hidonic or oleic acids reversibly depressed Na+ channel conductance an d shifted the inactivation curve to hyperpolarizing potentials. These effects were not prevented by inhibitors of lipoxygenase, cyclooxygena se, cytochrome P-450 epoxygenase, or protein kinase C. Neither palmiti c acid nor methyl ester oleate had an effect on the inward Na+ current , suggesting that trivial variations in membrane fluidity are not resp onsible for the Na+ current depression or kinetic changes. Arachidonic acid altered fast Na+ inactivation without changing the slow inactiva tion kinetics. Moreover, skeletal muscle Na+ channel gating currents w ere markedly decreased by 2 mu M arachidonic acid. Finally, nonstation ary noise analysis indicated that both the number of channels and tile 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-g ated Nat 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.