MinK endows the I(Ks) potassium channel pore with sensitivity to internal tetraethylammonium.
I(Ks) channels are heteromeric complexes of pore-forming KvLQT1 subunits and pore-associated MinK subunits. Channels formed only of KvLQT1 subunits vary from I(Ks) channels in their gating kinetics, single-channel conductance, and ion selectivity. Here we show that I(Ks) channels are more sensitive to blockade by internal tetraethylammonium ion (TEA) than KvLQT1 channels. Inhibition by internal TEA is shown to proceed by a simple bimolecular interaction in the I(Ks) conduction pathway. Application of a noise-variance strategy suggests that MinK enhances blockade by increasing the dwell time of TEA on its pore site from approximately 70 to 370 micros. Mutation of consecutive residues across the single transmembrane segment of MinK identifies positions that alter TEA blockade of I(Ks) channels. MinK is seen to determine the pharmacology of I(Ks) channels in addition to establishing their biophysical attributes.
Sesti
F
F
Section of Developmental Biology and Biophysics, Departments of Pediatrics and Cellular and Molecular Physiology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536 USA.
Tai
K K
KK
Goldstein
S A
SA
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007700:Kinetics; D046911:Macromolecular Substances; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D019789:Tetraethylammonium / Q000494:pharmacology*; D014982:Xenopus laevis
D046911:Macromolecular Substances; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; C059983:potassium channel protein I(sk); D019789:Tetraethylammonium