Modulation of muscle rNav1.4 Na⁺ channel isoform by arachidonic acid and its non‐metabolized analog

Arachidonic acid (AA) and its metabolic products are important second messengers which exert many biological actions, including modulation of various ion channels. However, the blockage of muscle Na(+) channel isoforms by AA has not been examined in detail. Here, we investigated the modulating effects of AA on muscle rNa(V)1.4 isoforms expressed in human embryonic kidney 293 cells. The results revealed that AA has both activation and inhibitory effects on rNa(V)1.4 currents depending on the depolarizing potential: AA increased the rNa(V)1.4 current evoked by a depolarization of -30 or -40 mV, but significantly decreased the rNa(V)1.4 current evoked by a depolarization of membrane potential over -10 mV. At concentrations of 1-500 microM, the inhibitory effect on the rNa(V)1.4 current induced by AA was dose-dependent and reversible. In addition to modulating the amplitude of the rNa(V)1.4 current, AA significantly modulated the steady-state activation and inactivation properties of rNa(V)1.4 channels. Furthermore, treatment with AA resulted in a fairly slow recovery of the rNa(V)1.4 channel from inactivation; however, the inhibitory effect of AA was not changed by repetitive pulses or by changing frequency. The effect of AA on rNa(V)1.4 currents was completely mimicked by ETYA, the non-metabolized analog of AA. Our data demonstrated that AA, but not the metabolic products of AA, can voltage-dependent modulate rNa(V)1.4 currents.