A novel N-terminal motif of dipeptidyl peptidase-like proteins produces rapid inactivation of KV4.2 channels by a pore-blocking mechanism

Channels (Austin). 2009 Nov;3(6):448-61. doi: 10.4161/chan.3.6.10216. Epub 2009 Nov 30.


The somatodendritic subthreshold A-type K(+) current in neurons (I(SA)) depends on its kinetic and voltage-dependent properties to regulate membrane excitability, action potential repetitive firing, and signal integration. Key functional properties of the K(V)4 channel complex underlying I(SA) are determined by dipeptidyl peptidase-like proteins known as dipeptidyl peptidase 6 (DPP6) and dipeptidyl peptidase 10 (DPP10). Among the multiple known DPP10 isoforms with alternative N-terminal sequences, DPP10a confers exceptionally fast inactivation to K(V)4.2 channels. To elucidate the molecular basis of this fast inactivation, we investigated the structure-function relationship of the DPP10a N-terminal region and its interaction with the K(V)4.2 channel. Here, we show that DPP10a shares a conserved N-terminal sequence (MNQTA) with DPP6a (aka DPP6-E), which also induces fast inactivation. Deletion of the NQTA sequence in DPP10a eliminates this dramatic fast inactivation, and perfusion of MNQTA peptide to the cytoplasmic face of inside-out patches inhibits the K(V)4.2 current. DPP10a-induced fast inactivation exhibits competitive interactions with internally applied tetraethylammonium (TEA), and elevating the external K(+) concentration accelerates recovery from DPP10a-mediated fast inactivation. These results suggest that fast inactivation induced by DPP10a or DPP6a is mediated by a common N-terminal inactivation motif via a pore-blocking mechanism. This mechanism may offer an attractive target for novel pharmacological interventions directed at impairing I(SA) inactivation and reducing neuronal excitability.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Conserved Sequence
  • DNA, Complementary
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / physiology*
  • Neurons / metabolism
  • Oocytes
  • Patch-Clamp Techniques
  • Plasmids
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Shal Potassium Channels / antagonists & inhibitors*
  • Xenopus laevis


  • DNA, Complementary
  • Shal Potassium Channels
  • DPP6 protein, rat
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases