Journal article
A Cation–π Interaction between Extracellular TEA and an Aromatic Residue in Potassium Channels
The Journal of general physiology, Vol.128(6), pp.649-657
12/01/2006
DOI: 10.1085/jgp.200609654
PMCID: PMC2151593
PMID: 17130518
Abstract
Open-channel blockers such as tetraethylammonium (TEA) have a long history as probes of the permeation pathway of ion channels. High affinity blockade by extracellular TEA requires the presence of an aromatic amino acid at a position that sits at the external entrance of the permeation pathway (residue 449 in the eukaryotic voltage-gated potassium channel Shaker). We investigated whether a cation–π interaction between TEA and such an aromatic residue contributes to TEA block using the in vivo nonsense suppression method to incorporate a series of increasingly fluorinated Phe side chains at position 449. Fluorination, which is known to decrease the cation–π binding ability of an aromatic ring, progressively increased the inhibitory constant Ki for the TEA block of Shaker. A larger increase in Ki was observed when the benzene ring of Phe449 was substituted by nonaromatic cyclohexane. These results support a strong cation–π component to the TEA block. The data provide an empirical basis for choosing between Shaker models that are based on two classes of reported crystal structures for the bacterial channel KcsA, showing residue Tyr82 in orientations either compatible or incompatible with a cation–π mechanism. We propose that the aromatic residue at this position in Shaker is favorably oriented for a cation–π interaction with the permeation pathway. This choice is supported by high level ab initio calculations of the predicted effects of Phe modifications on TEA binding energy.
Details
- Title: Subtitle
- A Cation–π Interaction between Extracellular TEA and an Aromatic Residue in Potassium Channels
- Creators
- Christopher A Ahern - Department of Molecular Physiology and Biophysics, Jefferson Medical College, Philadelphia, PA 19107Amy L Eastwood - Division of Chemistry and Chemical EngineeringHenry A Lester - Division of Biology, California Institute of Technology, Pasadena, CA 91125Dennis A Dougherty - Division of Chemistry and Chemical EngineeringRichard Horn - Department of Molecular Physiology and Biophysics, Jefferson Medical College, Philadelphia, PA 19107
- Resource Type
- Journal article
- Publication Details
- The Journal of general physiology, Vol.128(6), pp.649-657
- DOI
- 10.1085/jgp.200609654
- PMID
- 17130518
- PMCID
- PMC2151593
- NLM abbreviation
- J Gen Physiol
- ISSN
- 0022-1295
- eISSN
- 1540-7748
- Language
- English
- Date published
- 12/01/2006
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984070320402771
Metrics
28 Record Views