The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels.
Auxiliary beta-subunits dictate the physiological properties of voltage-gated K(+) (K(V)) channels in excitable tissues. In many instances, however, the underlying mechanisms of action are poorly understood. The dipeptidyl-aminopeptidase-like protein 6 (DPP6) is a specific beta-subunit of neuronal K(V)4 channels, which may promote gating through interactions between the single transmembrane segment of DPP6 and the channel's voltage sensing domain (VSD). A combination of gating current measurements and protein biochemistry (in-vitro translation and co-immunoprecipitations) revealed preferential physical interaction between the isolated K(V)4.2-VSD and DPP6. Significantly weaker interactions were detected between DPP6 and K(V)1.3 channels or the K(V)4.2 pore domain. More efficient gating charge movement resulting from a direct interaction between DPP6 and the K(V)4.2-VSD is unique among the known actions of K(V) channel beta-subunits. This study shows that the modular VSD of a K(V) channel can be directly regulated by transmembrane protein-protein interactions involving an extrinsic beta-subunit. Understanding these interactions may shed light on the pathophysiology of recently identified human disorders associated with mutations affecting the dpp6 gene.
Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA.
Kevin
K
Dougherty
Liwei
L
Tu
Carol
C
Deutsch
Manuel
M
Covarrubias
D000818:Animals; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D004594:Electrophysiology; D006801:Humans; D015640:Ion Channel Gating; D051664:Kv1.3 Potassium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000737:chemistry* / Q000502:physiology; D010447:Peptide Hydrolases / Q000378:metabolism / Q000502:physiology*; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D021122:Protein Subunits; D051672:Shal Potassium Channels / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D051664:Kv1.3 Potassium Channel; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D021122:Protein Subunits; D051672:Shal Potassium Channels; C503535:DPP6 protein, human; D010447:Peptide Hydrolases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases