Activation of ERG2 potassium channels by the diphenylurea NS1643.
Three members of the ERG potassium channel family have been described (ERG1-3 or Kv 11.1-3). ERG1 is by far the best characterized subtype and it constitutes the molecular component of the cardiac I(Kr) current. All three channel subtypes are expressed in neurons but their function remains unclear. The lack of functional information is at least partly due to the lack of specific pharmacological tools. The compound NS1643 has earlier been reported as an ERG1 channel activator. We found that NS1643 also activates the ERG2 channel; however, the molecular mechanism of the activation differs between the ERG1 and ERG2 channels. This is surprising since ERG1 and ERG2 channels have very similar biophysical and structural characteristics. For ERG2, NS1643 causes a left-ward shift of the activation curve, a faster time-constant of activation and a slower time-constant of inactivation as well as an increased relative importance for the fast component of deactivation to the total deactivation. In contrast, for ERG1, NS1643 causes a right-ward shift in the voltage-dependent release from inactivation but does not affect time-constants of deactivation. Because of these differences in the responses of ERG1 and ERG2 to NS1643, NS1643 can be used as a pharmacological tool to address ERG channel function. It may be useful for revealing physiological functions of ERG channels in neuronal tissue as well as to elucidate the structure-function relationships of the ERG channels.
Elmedyb
Pernille
P
The Danish National Research Foundation Centre for Cardiac Arrhythmia, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
Olesen
Søren-Peter
SP
Grunnet
Morten
M
D000818:Animals; D003001:Cloning, Molecular / Q000379:methods; D003408:Cresols / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D010671:Phenylurea Compounds / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014982:Xenopus laevis
D003408:Cresols; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D010671:Phenylurea Compounds; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea