KChIP4a regulates Kv4.2 channel trafficking through PKA phosphorylation.
Voltage-gated potassium (Kv) channels play important roles in regulating the excitability of myocytes and neurons. Kv4.2 is the primary alpha-subunit of the channel that produces the A-type K(+) current in CA1 pyramidal neurons of the hippocampus, which is critically involved in the regulation of dendritic excitability and plasticity. K(+) channel-interacting proteins, KChIPs (KChIP1-4), associate with the N-terminal of Kv4.2 and modulate the channel's biophysical properties, turnover rate and surface expression. In the present study, we investigated the role of Kv4.2 C-terminal PKA phosphorylation site S552 in the KChIP4a-mediated effects on Kv4.2 channel trafficking. We found that while interaction between Kv4.2 and KChIP4a does not require PKA phosphorylation of Kv4.2(S552), phosphorylation of this site is necessary for both enhanced stabilization and membrane expression of Kv4.2 channel complexes produced by KChIP4a. Enhanced surface expression and protein stability conferred by co-expression of Kv4.2 with other KChIP isoforms did not require PKA phosphorylation of Kv4.2 S552. Finally, we identify A-kinase anchoring proteins (AKAPs) as Kv4.2 binding partners, allowing for discrete local PKA signaling. These data demonstrate that PKA phosphorylation of Kv4.2 plays an important role in the trafficking of Kv4.2 through its specific interaction with KChIP4a.
Lin
Lin
L
Molecular Neurophysiology and Biophysics Unit, Laboratory of Cellular and Synaptic Neurophysiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Sun
Wei
W
Wikenheiser
Andrew M
AM
Kung
Faith
F
Hoffman
Dax A
DA
D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism*
D054758:A Kinase Anchor Proteins; C455273:Kcnip4 protein, mouse; D051605:Kv Channel-Interacting Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D051672:Shal Potassium Channels; D017868:Cyclic AMP-Dependent Protein Kinases