PKA Modulation of Kv4.2-Encoded A-Type Potassium Channels Requires Formation of a Supramolecular Complex

• Published in: The Journal of neuroscience 2002-12, Vol.22 (23), p.10123-10133
• Main Authors: Schrader, Laura A, Anderson, Anne E, Mayne, Amber, Pfaffinger, Paul J, Sweatt, John David
• Format: Article
• Language: English
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Amino Acid Substitution; Animals; Binding Sites - genetics; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Colforsin - analogs & derivatives; Colforsin - pharmacology; COS Cells; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - metabolism; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Kv Channel-Interacting Proteins; Macromolecular Substances; Mutagenesis, Site-Directed; Oocytes - drug effects; Oocytes - metabolism; Patch-Clamp Techniques; Phosphopeptides - metabolism; Phosphorylation; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Voltage-Gated; Protein Subunits - metabolism; Repressor Proteins; Shal Potassium Channels; Structure-Activity Relationship; Transfection; Xenopus laevis
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.22-23-10123.2002

A-type channels, encoded by the pore-forming alpha-subunits of the Kv4.x family, are particularly important in regulating membrane excitability in the CNS and the heart. Given the key role of modulation of A currents by kinases, we sought to investigate the protein structure-function relationships underlying the regulation of these currents by PKA. We have previously shown the existence of two PKA phosphorylation sites in the Kv4.2 sequence; therefore, we focused this study on the Kv4.2 primary subunit. In the present studies we made the surprising finding that PKA phosphorylation of the Kv4.2 alpha-subunit is necessary but not sufficient for channel modulation; channel modulation by PKA required the presence of an ancillary subunit, the K+ channel interacting protein (KChIP3). Therefore, these findings indicate a surprising complexity to kinase regulation of A currents, in that an interaction of two separate molecular events, alpha-subunit phosphorylation and the association of an ancillary subunit (KChIP3), are necessary for phosphorylation-dependent regulation of Kv4.2-encoded A channels by PKA. Overall, our studies indicate that PKA must of necessity act on a supramolecular complex of pore-forming alpha-subunits plus ancillary subunits to alter channel properties.