Activation of transient receptor potential vanilloid 4 (TRPV4) can increase hippocampal neuronal excitability. TRPV4 has been reported to be involved in the pathogenesis of epilepsy. Voltage‐gated potassium channels (VGPCs) play an important role in regulating neuronal excitability and abnormal VGPCs expression or function is related to epilepsy. Here, we examined the effect of TRPV4 activation on the delayed rectifier potassium current (I_K) in hippocampal pyramidal neurons and on the Kv subunits expression in male mice. We also explored the role of TRPV4 in changes in Kv subunits expression in male mice following pilocarpine‐induced status epilepticus (PISE). Application of TRPV4 agonists, GSK1016790A and 5,6‐EET, markedly reduced I_K in hippocampal pyramidal neurons and shifted the voltage‐dependent inactivation curve to the hyperpolarizing direction. GSK1016790A‐ and 5,6‐EET‐induced inhibition of I_K was blocked by TRPV4 specific antagonists, HC‐067047 and RN1734. GSK1016790A‐induced inhibition of I_K was markedly attenuated by calcium/calmodulin‐dependent kinase II (CaMKII) antagonist. Application of GSK1016790A for up to 1 hr did not change the hippocampal protein levels of Kv1.1, Kv1.2, or Kv2.1. Intracerebroventricular injection of GSK1016790A for 3 d reduced the hippocampal protein levels of Kv1.2 and Kv2.1, leaving that of Kv1.1 unchanged. Kv1.2 and Kv2.1 protein levels as well as I_K reduced markedly in hippocampi on day 3 post PISE, which was significantly reversed by HC‐067047. We conclude that activation of TRPV4 inhibits I_K in hippocampal pyramidal neurons, possibly by activating CaMKII. TRPV4‐induced decrease in Kv1.2 and Kv2.1 expression and I_K may be involved in the pathological changes following PISE.

中文翻译：

---

瞬时受体电位香草素 4 激活抑制海马锥体神经元延迟整流钾通道：对毛果芸香碱诱导的癫痫持续状态后病理变化的影响

瞬时受体电位香草素 4 (TRPV4) 的激活可以增加海马神经元的兴奋性。据报道，TRPV4 参与癫痫的发病机制。电压门控钾通道（VGPCs）在调节神经元兴奋性中起重要作用，VGPCs的异常表达或功能与癫痫有关。在这里，我们检查了 TRPV4 激活对海马锥体神经元延迟整流钾电流 ( I _K ) 和雄性小鼠 Kv 亚基表达的影响。我们还探讨了 TRPV4 在毛果芸香碱诱导的癫痫持续状态 (PISE) 后雄性小鼠 Kv 亚基表达变化中的作用。应用 TRPV4 激动剂 GSK1016790A 和 5,6-EET，显着降低I _K在海马锥体神经元中，电压依赖性失活曲线向超极化方向移动。GSK1016790A 和 5,6-EET 诱导的I _K抑制被 TRPV4 特异性拮抗剂 HC-067047 和 RN1734 阻断。GSK1016790A 诱导的I _K抑制被钙/钙调蛋白依赖性激酶 II (CaMKII) 拮抗剂显着减弱。应用 GSK1016790A 长达 1 小时不会改变 Kv1.1、Kv1.2 或 Kv2.1 的海马蛋白水平。脑室内注射 GSK1016790A 3 d 降低了 Kv1.2 和 Kv2.1 的海马蛋白水平，而 Kv1.1 的海马蛋白水平保持不变。Kv1.2 和 Kv2.1 蛋白水平以及I _KPISE 后第 3 天海马体中的显着减少，这被 HC-067047 显着逆转。我们的结论TRPV4抑制的激活我_ķ海马锥体神经元，可能通过激活CaMKII的。TRPV4 诱导的 Kv1.2 和 Kv2.1 表达和I _{K 的降低}可能与 PISE 后的病理变化有关。