Extracellular Blockade of Potassium Channels by TEA⁺: The Tip of the Iceberg?

Extracellular blockade of potassium channels by TEA⁺ has long been an important tool in electrophysiology (Armstrong, 1969). It is known that the binding affinity of TEA⁺ for the external side is directly affected by the amino acid side chain at position 449 (Shaker) (Heginbotham and MacKinnon, 1992). If an aromatic side chain is present (Tyr or Phe), TEA⁺ binding is strong, whereas there is a loss of affinity for almost any other side chain (Trp, Val, Thr, etc.). This has led to the suggestion that some amount of cation-π electron interaction was involved in the stabilization of the TEA⁺ at the external site. In classical terms, this interaction corresponds roughly to the favorable attraction between a positive charge and the quadrupolar moment of the aromatic ring. In broad agreement with the experimental data on external TEA^+...