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Am J Physiol Cell Physiol (October 26, 2005). doi:10.1152/ajpcell.00358.2005
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Submitted on July 18, 2005
Accepted on October 19, 2005

ERK/MAPK Regulates the Kv4.2 Potassium Channel by Direct Phosphorylation of the Pore-forming Subunit

Laura A Schrader1*, Shari G Birnbaum1, Brian M Nadin1, Yajun Ren2, Duy Bui1, Anne E Anderson3, and J. David Sweatt1

1 Neuroscience, Baylor College of Medicine, Houston, TX, USA
2 Pediatrics and Neurology, Baylor College of Medicine, Houston, TX, USA
3 Neuroscience, Baylor College of Medicine, Houston, TX, USA; Pediatrics and Neurology, Baylor College of Medicine, Houston, TX, USA

* To whom correspondence should be addressed. E-mail: schrader{at}tulane.edu.

Kv4.2 is the primary pore-forming subunit encoding A-type currents in many neurons throughout the nervous system, and also contributes to the Ito 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 have previously shown that Kv4.2 is directly phosphorylated at 3 sites by ERK/MAPK (Threonine 602, Threonine 607 and Serine 616). 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 phospho-site 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 to wildtype. Surprisingly, the S616D mutation caused the opposite effect, a leftward shift in the activation voltage. KChIP3 ancillary subunit coexpression with Kv4.2 was necessary for the 607D effect, as the 607D mutant when expressed in the absence of KChIP3 was not different from wildtype 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 MAP kinase regulation of membrane ion channels.




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