Auxiliary KChIP4a suppresses A-type K+ current through endoplasmic reticulum (ER) retention and promoting closed-state inactivation of Kv4 channels

J Biol Chem. 2013 May 24;288(21):14727-41. doi: 10.1074/jbc.M113.466052. Epub 2013 Apr 10.


In the brain and heart, auxiliary Kv channel-interacting proteins (KChIPs) co-assemble with pore-forming Kv4 α-subunits to form a native K(+) channel complex and regulate the expression and gating properties of Kv4 currents. Among the KChIP1-4 members, KChIP4a exhibits a unique N terminus that is known to suppress Kv4 function, but the underlying mechanism of Kv4 inhibition remains unknown. Using a combination of confocal imaging, surface biotinylation, and electrophysiological recordings, we identified a novel endoplasmic reticulum (ER) retention motif, consisting of six hydrophobic and aliphatic residues, 12-17 (LIVIVL), within the KChIP4a N-terminal KID, that functions to reduce surface expression of Kv4-KChIP complexes. This ER retention capacity is transferable and depends on its flanking location. In addition, adjacent to the ER retention motif, the residues 19-21 (VKL motif) directly promote closed-state inactivation of Kv4.3, thus leading to an inhibition of channel current. Taken together, our findings demonstrate that KChIP4a suppresses A-type Kv4 current via ER retention and enhancement of Kv4 closed-state inactivation.

Keywords: Closed-state Inactivation; Confocal Microscopy; Electrophysiology; Endoplasmic Reticulum (ER); Gating; KChIPs; Kv4; Neurobiology; Potassium Channels; Trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • HEK293 Cells
  • Humans
  • Ion Transport / physiology
  • Kv Channel-Interacting Proteins / genetics
  • Kv Channel-Interacting Proteins / metabolism*
  • Potassium / metabolism*
  • Protein Structure, Tertiary
  • Shal Potassium Channels / antagonists & inhibitors
  • Shal Potassium Channels / genetics
  • Shal Potassium Channels / metabolism*


  • Kv Channel-Interacting Proteins
  • Shal Potassium Channels
  • Potassium