Background: 

Non-receptor tyrosine kinases (PTKs) and non-receptor tyrosine phosphatases (PTPs) have been implicated in the regulation of ion channels, neuronal excitability and synaptic plasticity. We previously showed that PTKs such as Src kinase, and PTPs such as PTPa and PTPe modulate the activity of delayed-rectifier K⁺ channels (IK).

Results and methods: 

Here we show cultured cortical neurons from PTPe knockout (EKO) mice to exhibit increased excitability when compared to wild type (WT) mice, with larger spike discharge frequency, enhanced fast after-hyperpolarization (fAHP), increased after- depolarization (ADP) and reduced spike width. A decrease in IK and a rise in large-conductance Ca²⁺-activated K⁺ currents (mBK) were observed in EKO cortical neurons compared to WT. Parallel studies in transfected CHO cells indicate that Kv1.1, Kv1.2, Kv7.2/7.3 and mBK are plausible molecular correlates of this multi-faceted modulation of K⁺ channels by PTPe. In CHO cells, Kv1.1, Kv1.2 and Kv7.2/7.3 K⁺ currents were upregulated by PTPe, while mBK channel activity was reduced. The levels of tyrosine phosphorylation of Kv1.1, Kv1.2, Kv7.3 and mBK potassium channels were increased in the brain cortices of neonatal and adult EKO mice, compared to WT, suggesting that PTPe in the brain modulates these channel proteins.

Conclusions: 

Our data indicate that in EKO mice, the lack of PTPe-mediated dephosphorylation of Kv1.1, Kv1.2 and Kv7.3 leads to decreased IK density and enhanced ADP. In addition, the deficient PTPe-mediated dephosphorylation of mBK channels likely contributes to enhanced mBK and fAHP, spike shortening and consequent increase in neuronal excitability observed in cortical neurons from EKO mice.