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

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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 1996
Externally publishedYes

Fingerprint

Tetraethylammonium
Potassium Channels
Structure-Activity Relationship
Ammonium Compounds
Binding Sites
Ions
Electrons
Xenopus
Hydroxyl Radical
Oocytes
Tyrosine
Cations

ASJC Scopus subject areas

  • Pharmacology

Cite this

Structure-activity relationship of quaternary ammonium ions at the external tetraethylammonium binding site of cloned potassium channels. / Jarolimek, W.; Soman, K. V.; Alam, M.; Brown, A. M.

In: Molecular Pharmacology, Vol. 49, No. 1, 01.1996, p. 165-171.

Research output: Contribution to journalArticle

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