Kv42 As an Effector for ERK

Recent research suggests that ERK modifies transient A-type potassium currents. Johnston and colleagues have demonstrated that MEK inhibitor application leads to downregulation of A-type K+ currents in CA1 hippocampal dendrites. Both PD098059 and U0126 produce a hyperpolarizing shift in the activation curve for this current and block the enhancement in back-propagating action potential amplitude observed in response to activators of PKA and PKC (Yuan, et al, submitted). These findings suggest a role for ERK in the modulation of dendritic A-type potassium currents.

While the identity of the K+ channel subunits responsible for this transient A-type K+ current is currently unknown, evidence points to the Shal-type Kv4.2 channels as the leading candidate to mediate these currents. One of two transient K+ channels found in the hippocampus, Kv4.2 is abundantly expressed in somatic and dendritic regions of hippocampal pyramidal neurons in area CA1.89 At the ultrastructural level, these channels are predominately localized on the postsynaptic membrane associated with presynaptic terminals.6

Examination of the Kv4.2 amino acid sequence has revealed consensus sites on the C-terminal domain suitable for phosphorylation by ERK. Using phospho-specific antibodies generated against the channel at putative ERK phosphorylation sites, Kv4.2 appears to be an excellent substrate for ERK in the hippocampus. Using this antibody, immunohistochemical studies have exposed a fascinating pattern of input-specific labeling in the hippocampus, with high levels of staining in stratum radiatum and sparse labeling in stratum pyramidale.99 In addition, recent studies have demonstrated ERK-dependent phosphorylation of Kv4.2 in hippocampal area CA1 following activation of ERK by PKA, PKC and P-adrenergic receptor stimulation (Adams et al,

Figure 2. Working model. This model, as discussed in the text, highlights three potential sites of action for ERK in LTP and learning and memory. To summarize:

• ERK may phosphorylate Kv4.2, thereby downregulating K+ currents and essentially amplifying individual EPSPs. The larger EPSPs signaling to the soma could cause action potential generation.

• Action potentials initiated in the axon back-propagate into the dendrites. Again, ERK phosphorylation of Kv4.2 could relieve the dampening effect that K+ currents have on these backpropagating action potentials. A larger depolarization in the dendrite resulting from the larger action potential could remove the Mg++ block from NMDA receptor allowing for calcium influx.

• The calcium entry via NMDA receptor-mediated channels could activate ERK via one of the pathways shown above. A possible third site of action could be phosphorylation of the transcription factor CREB leading to changes in gene expression.

Figure 2. Working model. This model, as discussed in the text, highlights three potential sites of action for ERK in LTP and learning and memory. To summarize:

• ERK may phosphorylate Kv4.2, thereby downregulating K+ currents and essentially amplifying individual EPSPs. The larger EPSPs signaling to the soma could cause action potential generation.

• Action potentials initiated in the axon back-propagate into the dendrites. Again, ERK phosphorylation of Kv4.2 could relieve the dampening effect that K+ currents have on these backpropagating action potentials. A larger depolarization in the dendrite resulting from the larger action potential could remove the Mg++ block from NMDA receptor allowing for calcium influx.

• The calcium entry via NMDA receptor-mediated channels could activate ERK via one of the pathways shown above. A possible third site of action could be phosphorylation of the transcription factor CREB leading to changes in gene expression.

unpublished observations). Taken together, these studies identify phosphorylation of Kv4.2 by ERK as an attractive potential mechanism underlying modulation ofA-type K+ currents, and by this mechanism regulate the triggering of synaptic plasticity and memory formation (Fig. 2).

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