Mechanism of modulation of the voltage-gated skeletal and cardiac muscle sodium channels by fatty acids
Mechanism of modulation of the voltage-gated skeletal and cardiac muscle sodium channels by fatty acids
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DOI：
10.1152/ajpcell.1997.272.2.c592
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发表时间：
1997-02-01
影响因子：
5.5
通讯作者：
Agnew, WS
中科院分区：
文献类型：
--
作者：
Bendahhou, S;Cummins, TR;Agnew, WS
外源性不饱和脂肪酸对大鼠骨骼肌和心脏Na+通道的调控作用应用1-10 μ M花生四烯酸或油酸可逆地抑制Na+通道电导和移动失活曲线超极化电位。脂氧合酶、环氧合酶、细胞色素P-450环氧合酶或蛋白激酶C的抑制剂不能阻止这些作用。棕榈酸和油酸甲酯对内向Na+电流都没有影响，这表明膜流动性的微小变化不负责Na+电流的抑制或动力学变化。花生四烯酸改变快速钠+失活，而不改变缓慢失活动力学。此外，骨骼肌Na+通道门控电流显着降低2 μ M花生四烯酸。最后，非稳态噪声分析表明，通道数量和开放概率都略有减少，而单通道电导没有变化。这些数据表明，不饱和脂肪酸如花生四烯酸和油酸1）特异性调节电压门控Nat通道，2）可能在脂肪酸结合结构域直接与Na+通道相互作用，通过减少总门控电荷和改变快速失活动力学。
Voltage-gated rat skeletal muscle and cardiac Na+ channels are modulated by exogenous unsaturated fatty acids. Application of 1-10 mu M 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 mu M 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 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.