ERK/MAPK regulates the Kv4.2 potassium channel by direct phosphorylation of the pore-forming subunit

Abstract

regulates the Kv4.2 potassium channel by direct phosphorylation of the pore-forming subunit. Am J Physiol Cell Physiol 290: C852-C861, 2006. First published October 26, 2005 doi:10.1152 doi:10. /ajpcell.00358.2005.2 is the primary pore-forming subunit encoding A-type currents in many neurons throughout the nervous system, and it also contributes to the transient outward currents of cardiac myocytes. A-type currents in the dendrites of hippocampal CA1 pyramidal neurons are regulated by activation of ERK/MAPK, and Kv4.2 is the likely pore-forming subunit of that current. We showed previously that Kv4.2 is directly phosphorylated at three sites by ERK/MAPK (T602, T607, and S616). In this study we determined whether direct phosphorylation of Kv4.2 by ERK/ MAPK is responsible for the regulation of the A-type current observed in neurons. We made site-directed mutants, changing the phosphosite serine (S) or threonine (T) to aspartate (D) to mimic phosphorylation. We found that the T607D mutation mimicked the electrophysiological changes elicited by ERK/MAPK activation in neurons: a rightward shift of the activation curve and an overall reduction in current compared with wild type (WT). Surprisingly, the S616D mutation caused the opposite effect, a leftward shift in the activation voltage. K ϩ channel-interacting protein (KChIP)3 ancillary subunit coexpression with Kv4.2 was necessary for the T607D effect, as the T607D mutant when expressed in the absence of KChIP3 was not different from WT Kv4.2. These data suggest that direct phosphorylation of Kv4.2 at T607 is involved in the dynamic regulation of the channel function by ERK/MAPK and an interaction of the primary subunit with KChIP is also necessary for this effect. Overall these studies provide new insights into the structure-function relationships for MAPK regulation of membrane ion channels. K ϩ channel-interacting protein; kinase; neurons; A-type current MANY STUDIES HAVE SHOWN THAT ERK is important for regulation of neuronal function, particularly playing a role in the regulation of synaptic plasticity and long-term memory formation (3,13,14,30,46,48). Considerable evidence is accumulating that ERK activation plays a role in the regulation of postsynaptic excitability, specifically operating in the context of synaptic plasticity (40,46,48). One potential mechanism of this regulation by ERK is indirect, by long-term modulation of cell properties through the control of gene transcription and regulation of channel gene expression (9). Another possible mechanism by which ERK might modulate neuronal excitability is through direct regulation of membrane ion channels that regulate the membrane potential and thereby intrinsic membrane properties.In our recent studies, we have focused on regulation of ion channels by ERK because modulation of excitability may be a critical factor that ultimately controls the induction of longlasting changes in synaptic strength. One possible direct target of ERK is the K ϩ channel Kv4.2, which encodes a transient A-type K ϩ current that...

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