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 implicat ed in the direct and indirect modulation of a spectrum of voltage-gate d ion channels, Skeletal muscle sodium channels can be either activate d or inhibited by FFA exposure; the response is dependent on both FFA structure and site of exposure. Recombi nant human skeletal muscle sod ium channels (hSkM1) were transfected into heterologous human renal ep ithelium HEK293t cells, Cytoplasmic delivery of 5 mu M AA augmented th e 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 mu 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 p eriod by 29% (+/- 13 S.E., n = 5), The increase in hSkM1 current was n ot accompanied by shifts in voltage dependence of activation, steady-s tate 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 chann els first noted in cultured muscle cells can be reproduced by expressi ng recombinant sodium channels in epithelial cells, Although the respo nses to applied FFAs could be direct or indirect, we suggest that: 1) SkM1 has two classes of response to FFA, one which produces augmentati on of macroscopic currents with intracellular FFA, and a second which produces inhibition with extracellular FFA; 2) H1 has only one class o f response, which produces inhibition with extracellular FFA, A testab le hypothesis is that the presence or absence of each response is due to a specific structure in SkM1 or H1. These specific structures may d irectly interact with FFA or may interact with intermediate components .