Arachidonic acid potently inhibits both postsynaptic-type Kv4.2 and presynaptic-type Kv1.4 IA potassium channels
Arachidonic acid potently inhibits both postsynaptic-type Kv4.2 and presynaptic-type Kv1.4 IA potassium channels
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DOI：
10.1111/j.1460-9568.2009.06737.x
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发表时间：
2009-05-01
影响因子：
3.4
通讯作者：
Mueller, Wolfgang S.
中科院分区：
文献类型：
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作者：
Angelova, Plamena R.;Mueller, Wolfgang S.
花生四烯酸 (AA) 是一种游离脂肪酸膜渗透性第二信使，通过受体和 Ca2+ 依赖性事件从细胞膜中释放出来。我们之前已经证明，极低的 [AA](i) (1 pm) 会抑制海马神经元中的突触后电压门控 K+ 电流 (I-A)。这种抑制作用被一些抗氧化剂阻断。体细胞树突 I-A 由 Kv4.2 基因产物介导，而突触前 I-A 由 Kv1.4 通道亚基介导。为了解决 AA 与这些 α 亚基的相互作用，我们使用全细胞电压钳记录研究了用 Kv1.4 或 Kv4.2 大鼠 cDNA 转染的人胚胎肾 293 细胞中 A 电流的调节。对于两种电流，1 pm [AA](i) 均抑制电导 > 50%。此外，AA 使失活的电压依赖性分别改变了 -9 (Kv1.4) 和 +6 mV (Kv4.2)。细胞内共同施用 Trolox C (10 μm)（一种抗氧化剂维生素 E 衍生物）仅减缓 AA 对振幅的影响。值得注意的是，Trolox C 将 Kv1.4 介导的 I-A 激活的电压依赖性改变了 -32 mV。细胞外 Trolox 持续 > 15 分钟抑制 AA 对 I-A 振幅的影响，以及细胞内 Trolox 对 Kv1.4 介导的 I-A 激活的电压依赖性的影响。细胞外 Trolox 进一步将 Kv4.2 激活的电压依赖性改变了 +33 mV。总之，AA对Kv4.2通道最大幅度的抑制可以解释海马神经元体树突I-A的抑制，而失活的电压依赖性的负移显然取决于其他神经元通道亚基。 AA 和 Trolox 均能有效调节 Kv1.4 和 Kv4.2 通道 α 亚基，从而可能调节突触传递和可塑性中的突触前递质释放和突触后体树突兴奋性。
Arachidonic acid (AA) is a free fatty acid membrane-permeable second messenger that is liberated from cell membranes via receptor- and Ca2+-dependent events. We have shown previously that extremely low [AA](i) (1 pm) inhibits the postsynaptic voltage-gated K+ current (I-A) in hippocampal neurons. This inhibition is blocked by some antioxidants. The somatodendritic I-A is mediated by Kv4.2 gene products, whereas presynaptic I-A is mediated by Kv1.4 channel subunits. To address the interaction of AA with these alpha-subunits we studied the modulation of A-currents in human embryonic kidney 293 cells transfected with either Kv1.4 or Kv4.2 rat cDNA, using whole-cell voltage-clamp recording. For both currents 1 pm [AA](i) inhibited the conductance by > 50%. In addition, AA shifted the voltage dependence of inactivation by -9 (Kv1.4) and +6 mV (Kv4.2), respectively. Intracellular co-application of Trolox C (10 mu m), an antioxidant vitamin E derivative, only slowed the effects of AA on amplitude. Notably, Trolox C shifted the voltage dependence of activation of Kv1.4-mediated I-A by -32 mV. Extracellular Trolox for > 15 min inhibited the AA effects on I-A amplitudes as well as the effect of intracellular Trolox on the voltage dependence of activation of Kv1.4-mediated I-A. Extracellular Trolox further shifted the voltage dependence of activation for Kv4.2 by +33 mV. In conclusion, the inhibition of maximal amplitude of Kv4.2 channels by AA can explain the inhibition of somatodendritic I-A in hippocampal neurons, whereas the negative shift in the voltage dependence of inactivation apparently depends on other neuronal channel subunits. Both AA and Trolox potently modulate Kv1.4 and Kv4.2 channel alpha-subunits, thereby presumably tuning presynaptic transmitter release and postsynaptic somatodendritic excitability in synaptic transmission and plasticity.