Structure-activity relationship of quaternary ammonium ions at the external tetraethylammonium binding site of cloned potassium channels

W. Jarolimek, K. V. Soman, M. Alam, A. M. Brown

    Research output: Contribution to journalArticle

    9 Scopus citations

    Abstract

    Changes in the chemical structure of the tetraethylammonium (TEA) ion reduce binding affinity at the external TEA receptor of outwardly rectifying potassium channels. To study the mechanism of selective binding, we applied a variety of hydrophilic quaternary ammonium (QA) ions to the noninactivating mutant of Shaker B T449Y, to Kv3.1, and to Kv3.1 mutants, expressed in Xenopus oocytes. In outside-out patches, QA ions in which ethyl groups of TEA were replaced by methyl groups had a lower affinity than TEA, whereas changes in binding affinity were minor when propyl groups were substituted for ethyl groups. All channels tested showed this pattern. Changes in free energy of binding correlated well with changes in the computed free energy of hydration of the TEA derivatives that we used. The affinity for TEA derivatives was reduced in Kv3.1Y407T, which is in support of the hypothesis that cation π- electron interaction is involved. Binding affinities of QA ions were higher in Kv3.1 Y407F than in the wild-type, suggesting that the hydroxyl groups of the tyrosines reduce QA binding. The rank order of potency of the QA ions toward the different channels studied was the same. These results indicate that external QA ions bind strongly to hydrophobic π-electron-rich functions. The selectivity, however, is determined by the physical properties of the QA ion.

    Original languageEnglish (US)
    Pages (from-to)165-171
    Number of pages7
    JournalMolecular pharmacology
    Volume49
    Issue number1
    StatePublished - Jan 1 1996

    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmacology

    Fingerprint Dive into the research topics of 'Structure-activity relationship of quaternary ammonium ions at the external tetraethylammonium binding site of cloned potassium channels'. Together they form a unique fingerprint.

  • Cite this