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A Cation–π Interaction between Extracellular TEA and an Aromatic Residue in Potassium Channels

Ahern, Christopher A. and Eastwood, Amy L. and Lester, Henry A. and Dougherty, Dennis A. and Horn, Richard (2006) A Cation–π Interaction between Extracellular TEA and an Aromatic Residue in Potassium Channels. Journal of General Physiology, 128 (6). pp. 649-657. ISSN 0022-1295. PMCID PMC2151593. https://resolver.caltech.edu/CaltechAUTHORS:AHEjgp06

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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–{pi} 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–{pi} 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–{pi} 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–{pi} mechanism. We propose that the aromatic residue at this position in Shaker is favorably oriented for a cation–{pi} 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://jgp.rupress.org/content/128/6/649.longPublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151593/PubMed CentralArticle
https://doi.org/10.1085/jgp.200609654DOIUNSPECIFIED
https://doi.org/10.1085/jgp.200609654DOIUNSPECIFIED
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2006 The Rockefeller University Press. RUP grants the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode. Submitted: 21 August 2006. Accepted: 27 October 2006. Published online Nov 27 2006. doi:10.1085/jgp.200609654 We thank Benoit Roux for extensive discussions and advice about Poisson-Boltzmann calculations, Carol Deutsch for comments on the manuscript, Adrian Gross for the gift of a TEAs-Cl sample, and Stephanie Huang, Purnima Deshpande, and Lindsey Ingleby for help with the oocytes. This research was sponsored by grants from the National Institutes of Health (GM079427, NS11756, and NS34407). Lawrence G. Palmer served as editor.
Funders:
Funding AgencyGrant Number
NIHGM079427
NIHNS11756
NIHNS34407
Issue or Number:6
PubMed Central ID:PMC2151593
Record Number:CaltechAUTHORS:AHEjgp06
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:AHEjgp06
Usage Policy:RUP grants the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode.
ID Code:6628
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:15 Dec 2006
Last Modified:02 Oct 2019 23:34

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