Calcium–Calmodulin-Dependent Kinase II Modulates Kv4.2 Channel Expression and Upregulates Neuronal A-Type Potassium Currents

Abstract

Calcium-calmodulin-dependent kinase II (CaMKII) has a long history of involvement in synaptic plasticity, yet little focus has been given to potassium channels as CaMKII targets despite their importance in repolarizing EPSPs and action potentials and regulating neuronal membrane excitability. We now show that Kv4.2 acts as a substrate for CaMKII in vitro and have identified CaMKII phosphorylation sites as Ser438 and Ser459. To test whether CaMKII phosphorylation of Kv4.2 affects channel biophysics, we expressed wild-type or mutant Kv4.2 and the K ϩ channel interacting protein, KChIP3, with or without a constitutively active form of CaMKII in Xenopus oocytes and measured the voltage dependence of activation and inactivation in each of these conditions. CaMKII phosphorylation had no effect on channel biophysical properties. However, we found that levels of Kv4.2 protein are increased with CaMKII phosphorylation in transfected COS cells, an effect attributable to direct channel phosphorylation based on site-directed mutagenesis studies. We also obtained corroborating physiological data showing increased surface A-type channel expression as revealed by increases in peak K ϩ current amplitudes with CaMKII phosphorylation. Furthermore, endogenous A-currents in hippocampal pyramidal neurons were increased in amplitude after introduction of constitutively active CaMKII, which results in a decrease in neuronal excitability in response to current injections. Thus CaMKII can directly modulate neuronal excitability by increasing cell-surface expression of A-type K ϩ channels.

Recording Temperature Affects the Excitability of Mouse Superficial Dorsal Horn Neurons, In Vitro

“…In dendrites I Ar attenuates backpropagating APs. Numerous studies have shown that during depolarizing current injections the shunting inhibition provided by I Ar increases rheobase, delays the onset of AP discharge, and increases interspike interval (Mitterdorfer and Bean 2002;Molineux et al 2005;Russier et al 2003;Varga et al 2004;Vydyanathan et al 2005). Our data suggest an additional role for I Ar , where the shunting inhibition actually prevents AP discharge in reluctant firing neurons altogether.…”

Deletion ofKv4.2Gene Eliminates Dendritic A-Type K+Current and Enhances Induction of Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons

“…The amplitude of the second transient represents the amount of whole-cell A-type current that is mediated by Kv4 channels. The difference between the first transient and the second transient represents the amount of Kv1-mediated current that would not be expected to recover from inactivation during the 100 ms hyperpolarization (Varga et al, 2004).…”

Modulation of h-Channels in Hippocampal Pyramidal Neurons by p38 Mitogen-Activated Protein Kinase

“…Setting our search parameters at the highest level of stringency produced the list of 12 kinases shown in Table 1. Of this list, three kinases had previously described actions on voltage-gated ion channels: protein kinase C (PKC), calcium/calmodulin-dependent protein kinase II (CAMKII), and p38 MAPK (Varga et al, 2004;Chen et al, 2005;Wittmack et al, 2005). Of the entire list, p38 MAPK had the highest score for likely HCN interactions, and was predicted to phosphorylate both HCN1 and HCN2.…”