DIFFERENTIAL MODULATION OF A SODIUM CONDUCTANCE IN SKELETAL-MUSCLE BY INTRACELLULAR AND EXTRACELLULAR FATTY-ACIDS

Voltage-activated sodium channels of cultured skeletal muscle show diametrically divergent responses to intracellular vs. extracellular exposure to free fatty acids. Intracellular exposure to 1-20-mu-M arachidonic acid increased the magnitude of voltage-activated sodium currents, but not potassium currents, in whole cell recordings of human primary muscle cells and in the C2C12 mouse cell line. Oleic and stearic acids also stimulated increased sodium currents. In contrast, extracellular exposure to 5-10-mu-M arachidonic acid reversibly inhibited inward currents. Externally applied oleic acid was a less effective inhibitor, and stearic acid (up to 20-mu-M) produced no inhibition. The difference in sodium current responses to intracellular vs. extracellular exposure indicates that fatty acids can modulate skeletal muscle sodium channel function by at least two different pathways.