PKA modulation of Kv4.2-encoded A-type potassium channels requires formation of a supramolecular complex

J Neurosci. 2002 Dec 1;22(23):10123-33. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Amino Acid Substitution
  • Animals
  • Binding Sites / genetics
  • COS Cells
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Colforsin / analogs & derivatives*
  • Colforsin / pharmacology
  • 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


  • Calcium-Binding Proteins
  • Enzyme Inhibitors
  • Kv Channel-Interacting Proteins
  • Macromolecular Substances
  • Phosphopeptides
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Protein Subunits
  • Repressor Proteins
  • Shal Potassium Channels
  • Colforsin
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Cyclic AMP-Dependent Protein Kinases
  • 1,9-dideoxyforskolin