title: Interaction of DPP10a with Kv4.3 channel complex results in a sustained current component of human transient outward current Ito.
abstract: The sustained component of the K(+) outward current in human atrial myocytes is believed to be due to the slowly inactivating ultra-rapid potassium current I Kur and not to the fast inactivating transient outward current Ito. Here we provide evidence for contribution of Ito to this late current due to the effects of dipeptidyl peptidase-like protein (DPP) 10 (DPP10a) interacting with Kv4.3 channels. We studied the late current component of Ito in human atrial myocytes and CHO cells co-expressing Kv4.3 or Kv4.3/KChIP2 (control) and DPP proteins using voltage-clamp technique and a pharmacological approach. A voltage dependent and slowly inactivating late current (43% of peak amplitude) could be observed in atrial myocytes. We found a similar current in CHO cells expressing Kv4.3/KChIP2 + DPP10a, but not in cells co-expressing Kv4.3 + DPP or Kv4.3/KChIP2 + DPP6-S. Assuming that DPP10a influences atrial Ito, we detected DPP10 expression of three alternatively spliced mRNAs, DPP10 protein and colocalization of Kv4.3 and DPP10 proteins in human atrial myocytes. DPP10a did not affect properties of expressed Kv1.5 excluding a contribution to the sustained IKur in atrial cells. To test for the contribution of Kv4-based Ito on sustained K(+) outward currents in human atrial myocytes, we used 4-AP to block IKur, in combination with Heteropoda toxin 2 to block Kv4 channels. We could clearly separate an Ito fraction of about 19% contributing to the late current in atrial myocytes. Thus, the interaction of DPP10a, expressed in human atrium, with Kv4.3 channels generates a sustained current component of Ito, which may affect late repolarization phase of atrial action potentials.
authors.affiliation: Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Turnow
authors.forename: K
authors.initials: K
authors.lastname: Metzner
authors.forename: D
authors.initials: D
authors.lastname: Cotella
authors.forename: M J
authors.initials: MJ
authors.lastname: Morales
authors.forename: M
authors.initials: M
authors.lastname: Schaefer
authors.forename: T
authors.initials: T
authors.lastname: Christ
authors.forename: U
authors.initials: U
authors.lastname: Ravens
authors.forename: E
authors.initials: E
authors.lastname: Wettwer
authors.forename: S
authors.initials: S
authors.lastname: Kämmerer
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006325:Heart Atria / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051672:Shal Potassium Channels / Q000378:metabolism*; D014162:Transfection
chemical_list: D051672:Shal Potassium Channels; C476879:DPP10 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases