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Kinetics of Tethering Quaternary Ammonium Compounds to K⁺ Channels

Robert O. Blaustein^1,2

¹ Department of Biochemistry, Brandeis University, Waltham, MA 02454
² Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, MA 02111

Address correspondence to Robert O. Blaustein, Tufts-New England Medical Center, Box 7868, 750 Washington St., Boston, MA 02111. Fax: (617) 636-0576; E-mail: robert.blaustein{at}tufts.edu

Polymeric maleimido–quaternary ammonium (QA) compounds have been shown to function as molecular tape measures when covalently tethered to external cysteine residues of a Shaker K⁺ channel (Blaustein R.O., P.A. Cole, C. Williams, and C. Miller. 2000. Nat. Struct. Biol. 7:309–311). For sufficiently long compounds, the cysteine–maleimide tethering reaction creates a high concentration, at the channel's pore, of a TEA-like moiety that irreversibly blocks current. This paper investigates a striking feature of the maleimide–cysteine tethering kinetics. Strong blockers—those that induce substantial levels (>80%) of irreversible inhibition of current—react with channel cysteines much more rapidly than weak blockers and, when delivered to channels with four cysteine targets, react with multiexponential kinetics. This behavior is shown to arise from the ability of a strong blocker to concentrate its maleimide end near a channel's cysteine target by exploiting the reversible pore-blocking affinity of its QA headgroup.

Key Words: Shaker • tetraethylammonium • block • affinity-label • maleimide

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