Department of Physiology, Nanjing Medical University, Nanjing, P.R. China.
Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.
J Neurosci Res. 2021 Mar;99(3):914-926. doi: 10.1002/jnr.24749. Epub 2020 Dec 4.
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 ) 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 in hippocampal pyramidal neurons and shifted the voltage-dependent inactivation curve to the hyperpolarizing direction. GSK1016790A- and 5,6-EET-induced inhibition of I was blocked by TRPV4 specific antagonists, HC-067047 and RN1734. GSK1016790A-induced inhibition of I 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 reduced markedly in hippocampi on day 3 post PISE, which was significantly reversed by HC-067047. We conclude that activation of TRPV4 inhibits I in hippocampal pyramidal neurons, possibly by activating CaMKII. TRPV4-induced decrease in Kv1.2 and Kv2.1 expression and I may be involved in the pathological changes following PISE.
瞬时受体电位香草酸 4（TRPV4）的激活可增加海马神经元兴奋性。TRPV4 已被报道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方面起着重要作用，异常的 VGPCs 表达或功能与癫痫有关。在这里，我们研究了 TRPV4 激活对海马锥体神经元延迟整流钾电流（I）的影响，以及 TRPV4 激活对匹罗卡品诱导的癫痫持续状态（PISE）后雄性小鼠 Kv 亚基表达变化的作用。我们还探讨了 TRPV4 在匹罗卡品诱导的癫痫持续状态后雄性小鼠 Kv 亚基表达变化中的作用。TRPV4 激动剂 GSK1016790A 和 5,6-EET 的应用显著降低了海马锥体神经元中的 I，并将电压依赖性失活曲线向超极化方向移动。TRPV4 特异性拮抗剂 HC-067047 和 RN1734 阻断了 GSK1016790A 和 5,6-EET 诱导的 I 抑制。钙/钙调蛋白依赖性激酶 II（CaMKII）拮抗剂显著减弱了 GSK1016790A 诱导的 I 抑制。GSK1016790A 应用长达 1 小时不会改变海马 Kv1.1、Kv1.2 或 Kv2.1 的蛋白水平。侧脑室注射 GSK1016790A 3 天可降低海马 Kv1.2 和 Kv2.1 的蛋白水平，而 Kv1.1 蛋白水平不变。PISE 后第 3 天，海马 Kv1.2 和 Kv2.1 蛋白水平以及 I 显著降低，HC-067047 显著逆转了这一变化。我们的结论是，TRPV4 的激活抑制了海马锥体神经元中的 I，可能是通过激活 CaMKII 实现的。TRPV4 诱导的 Kv1.2 和 Kv2.1 表达和 I 的减少可能与 PISE 后的病理变化有关。
