Molecular impact of MinK on the enantiospecific block of I(Ks) by chromanols.
Slowly activating I:(Ks) (KCNQ1/MinK) channels were expressed in Xenopous: oocytes and their sensitivity to chromanols was compared to homomeric KCNQ1 channels. To elucidate the contribution of the ss-subunit MinK on chromanol block, a formerly described chromanol HMR 1556 and its enantiomer S5557 were tested for enantio-specificity in blocking I:(Ks) and KCNQ1 as shown for the single enantiomers of chromanol 293B. Both enantiomers blocked homomeric KCNQ1 channels to a lesser extent than heteromeric I:(Ks) channels. Furthermore, we expressed both WT and mutant MinK subunits to examine the involvement of particular MinK protein regions in channel block by chromanols. Through a broad variety of MinK deletion and point mutants, we could not identify amino acids or regions where sensitivity was abolished or strikingly diminished (>2.5 fold). This could indicate that MinK does not directly take part in chromanol binding but acts allosterically to facilitate drug binding to the principal subunit KCNQ1.
Lerche
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C
Aventis Pharma Deutschland GmbH, Cardiovascular Diseases, 65926 Frankfurt a. M., Germany. Christian.Lerche@aventis.com
Seebohm
G
G
Wagner
C I
CI
Scherer
C R
CR
Dehmelt
L
L
Abitbol
I
I
Gerlach
U
U
Brendel
J
J
Attali
B
B
Busch
A E
AE
D000818:Animals; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008564:Membrane Potentials / Q000187:drug effects; D009154:Mutation; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D018075:RNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D013237:Stereoisomerism; D014981:Xenopus
D002839:Chromans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D018075:RNA, Complementary; C059983:potassium channel protein I(sk); C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman