The transmembrane beta-subunits KCNE1, KCNE2, and DPP6 modify pharmacological effects of the antiarrhythmic agent tedisamil on the transient outward current Ito.
Accessory beta-subunits modulate the pharmacology of ion channel blockers. The aim was to investigate differences in effects of the antiarrhythmic agent and open-channel blocker tedisamil on transient outward current I(to) (Kv4.3) when coexpressed with beta-subunits potassium voltage-gated channel, Isk-related family, member 1 (KCNE1), potassium voltage-gated channel, Isk-related family, member 2 (KCNE2), or dipeptidyl-aminopeptidase-like protein 6 (DPP6) which modulate I(to) kinetics. Tedisamil inhibited I(to) with IC(50) values of 16 microM for Kv4.3+KChIP2, 11 microM in the presence of KCNE1, and 14 microM for KCNE2. Values were higher in the presence of DPP6 or DPP6+KCNE2 (35 and 26 microM). K(d) values of tedisamil binding and rate constants were not affected by KCNE or DPP6. I(to) kinetics were accelerated by KCNE and DPP6, inactivation to a larger extent with DPP6. Tedisamil did not affect activation time course but apparently accelerated inactivation in all channel subunit combinations tested. Deletion of the intracellular domain of KCNE2 or DPP6 resulted in slowing of kinetics and increased tedisamil sensitivity (IC(50) 4 and 7 microM). It is concluded that apparent effects of DPP6 and deletion mutants (KCNE2 and DPP6) are due to the acceleration or slowing effects of the beta-subunits on I(to) kinetics.
Radicke
Susanne
S
Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology, Fetscherstr. 74, 01307, Dresden, Germany.
Cotella
Diego
D
Sblattero
Daniele
D
Ravens
Ursula
U
Santoro
Claudio
C
Wettwer
Erich
E
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003521:Cyclopropanes / Q000378:metabolism / Q000494:pharmacology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000502:physiology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000502:physiology*; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; D051672:Shal Potassium Channels; C059921:tedisamil; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases