title: AKAP79/150 impacts intrinsic excitability of hippocampal neurons through phospho-regulation of A-type K+ channel trafficking.
abstract: Kv4.2, as the primary α-subunit of rapidly inactivating, A-type voltage-gated K(+) (Kv) channels expressed in hippocampal CA1 pyramidal dendrites, plays a critical role in regulating their excitability. Activity-dependent trafficking of Kv4.2 relies on C-terminal protein kinase A (PKA) phosphorylation. A-kinase-anchoring proteins (AKAPs) target PKA to glutamate receptor and ion channel complexes to allow for discrete, local signaling. As part of a previous study, we showed that AKAP79/150 interacts with Kv4.2 complexes and that the two proteins colocalize in hippocampal neurons. However, the nature and functional consequence of their interaction has not been previously explored. Here, we report that the C-terminal domain of Kv4.2 interacts with an internal region of AKAP79/150 that overlaps with its MAGUK (membrane-associated guanylate kinase)-binding domain. We show that AKAP79/150-anchored PKA activity controls Kv4.2 surface expression in heterologous cells and hippocampal neurons. Consistent with these findings, disrupting PKA anchoring led to a decrease in neuronal excitability, while preventing dephosphorylation by the phosphatase calcineurin resulted in increased excitability. These results demonstrate that AKAP79/150 provides a platform for dynamic PKA regulation of Kv4.2 expression, fundamentally impacting CA1 excitability.
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Faith
authors.initials: F
authors.lastname: Kung
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dell'Acqua
authors.forename: Dax A
authors.initials: DA
authors.lastname: Hoffman
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000502:physiology*; D000200:Action Potentials; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D054731:PDZ Domains; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D051672:Shal Potassium Channels / Q000378:metabolism*
chemical_list: D054758:A Kinase Anchor Proteins; C415703:Akap5 protein, rat; D051672:Shal Potassium Channels; D017868:Cyclic AMP-Dependent Protein Kinases; D051528:Guanylate Kinases