A novel N-terminal motif of dipeptidyl peptidase-like proteins produces rapid inactivation of KV4.2 channels by a pore-blocking mechanism.
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.
Jerng
Henry H
HH
Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. hjerng@cns.bcm.tmc.edu
Dougherty
Kevin
K
Covarrubias
Manuel
M
Pfaffinger
Paul J
PJ
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D018076:DNA, Complementary; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010957:Plasmids; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors*; D014982:Xenopus laevis
D018076:DNA, Complementary; D051672:Shal Potassium Channels; C557320:DPP6 protein, rat; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases