Functional Differences Between Two Kv1.1 RNA Editing Isoforms: a Comparative Study on Neuronal Overexpression in Mouse Prefrontal Cortex

Mol Neurobiol. 2021 May;58(5):2046-2060. doi: 10.1007/s12035-020-02229-1. Epub 2021 Jan 7.

Abstract

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.

Keywords: Excitability; Isoform; Kv1.1; Overexpression; RNA editing.

MeSH terms

  • Animals
  • Kv1.1 Potassium Channel / genetics
  • Kv1.1 Potassium Channel / metabolism*
  • Memory, Short-Term / physiology
  • Mice
  • Motor Activity / physiology
  • Neurons / metabolism*
  • Prefrontal Cortex / metabolism*
  • RNA Editing
  • RNA Isoforms

Substances

  • RNA Isoforms
  • Kv1.1 Potassium Channel