Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Chang-gang-dong Road 250, Guangzhou, 510260, China.
Key Laboratory of Neurogenetics and Channelopathies of the Ministry of Education of China, Guangzhou, China.
Mol Neurobiol. 2021 May;58(5):2046-2060. doi: 10.1007/s12035-020-02229-1. Epub 2021 Jan 7.
The Shaker-related potassium channel Kv1.1 subunit has important implications for controlling neuronal excitabilities. A particular recoding by A-to-I RNA editing at I400 of Kv1.1 mRNA is an underestimated mechanism for fine-tuning the properties of Kv1.1-containing channels. Knowledge about functional differences between edited (I400V) and non-edited Kv1.1 isoforms is insufficient, especially in neurons. To understand their different roles, the two Kv1.1 isoforms were overexpressed in the prefrontal cortex via local adeno-associated virus-mediated gene delivery. The I400V isoform showed a higher competitiveness in membrane translocalization, but failed to reduce current-evoked discharges and showed weaker impact on spiking-frequency adaptation in the transduced neurons. The non-edited Kv1.1 overexpression led to slight elevations in both fast- and non-inactivating current components of macroscopic potassium current. By contrast, the I400V overexpression did not impact the fast-inactivating current component. Further isolation of Kv1.1-specific current by its specific blocker dendrotoxin-κ showed that both isoforms did result in significant increases in current amplitude, whereas the I400V was less efficient in contributing the fast-inactivating current component. Voltage-dependent properties of the fast-inactivating current component did not alter for both isoforms. For recovery kinetics, the I400V showed a significant acceleration of recovery from fast inactivation. The gene delivery of the I400V rather than the wild type exhibited anxiolytic activities, which was assessed by an open field test. These results suggest that the Kv1.1 RNA editing isoforms have different properties and outcomes, reflecting the functional and phenotypic significance of the Kv1.1 RNA editing in neurons.
Shaker 相关钾通道 Kv1.1 亚基对控制神经元兴奋性具有重要意义。Kv1.1 mRNA 在 I400 位的 A-to-I RNA 编辑的特定重编码是微调含 Kv1.1 通道特性的被低估的机制。关于编辑（I400V）和非编辑 Kv1.1 同工型之间功能差异的知识不足，特别是在神经元中。为了了解它们的不同作用，通过局部腺相关病毒介导的基因传递在额前皮质中过表达这两种 Kv1.1 同工型。I400V 同工型在膜易位方面表现出更高的竞争力，但未能减少电流诱发的放电，并且对转导神经元中的尖峰频率适应的影响较弱。非编辑 Kv1.1 的过表达导致宏观钾电流的快速和非失活电流成分的轻微升高。相比之下，I400V 的过表达对快速失活电流成分没有影响。通过其特异性阻断剂树突毒素-κ 进一步分离 Kv1.1 特异性电流表明，两种同工型都导致电流幅度的显著增加，而 I400V 在贡献快速失活电流成分方面效率较低。快速失活电流成分的电压依赖性特性没有改变。对于恢复动力学，I400V 显示出从快速失活中快速恢复的显著加速。I400V 的基因传递而不是野生型表现出抗焦虑活性，这通过开阔场试验进行评估。这些结果表明，Kv1.1 RNA 编辑同工型具有不同的特性和结果，反映了 Kv1.1 RNA 编辑在神经元中的功能和表型意义。
