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Calcium Block of Single Sodium Channels: Role of a Pore-Lining Aromatic Residue

Santarelli, Vincent P. and Eastwood, Amy L. and Dougherty, Dennis A. and Ahern, Christopher A. and Horn, Richard (2007) Calcium Block of Single Sodium Channels: Role of a Pore-Lining Aromatic Residue. Biophysical Journal, 93 (7). pp. 2341-2349. ISSN 0006-3495. PMCID PMC1965434. https://resolver.caltech.edu/CaltechAUTHORS:20170408-214441240

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Abstract

Extracellular Ca^(2+) ions cause a rapid block of voltage-gated sodium channels, manifest as an apparent reduction of the amplitude of single-channel currents. We examined the influence of residue Tyr-401 in the isoform rNa_V1.4 on both single-channel conductance and Ca^(2+) block. An aromatic residue at this position in the outer mouth of the pore plays a critical role in high-affinity block by the guanidinium toxin tetrodotoxin, primarily due to an electrostatic attraction between the cationic blocker and the system of π electrons on the aromatic face. We tested whether a similar attraction between small metal cations (Na^+ and Ca^(2+)) and this residue would enhance single-channel conductance or pore block, using a series of fluorinated derivatives of phenylalanine at this position. Our results show a monotonic decrease in Ca^(2+) block as the aromatic ring is increasingly fluorinated, a result in accord with a cation-π interaction between Ca^(2+) and the aromatic ring. This occurred without a change of single-channel conductance, consistent with a greater electrostatic effect of the π system on divalent than on monovalent cations. High-level quantum mechanical calculations show that Ca^(2+) ions likely do not bind directly to the aromatic ring because of the substantial energetic penalty of dehydrating a Ca^(2+) ion. However, the complex of a Ca^(2+) ion with its inner hydration shell, Ca^(2+)(H_2O)_6, interacts electrostatically with the aromatic ring in a way that affects the local concentration of Ca^(2+) ions in the extracellular vestibule.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1529/biophysj.107.106856DOIArticle
https://www.sciencedirect.com/science/article/pii/S0006349507714893PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1965434/PubMed CentralArticle
ORCID:
AuthorORCID
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2007 The Biophysical Society. Published by Elsevier. Received 20 February 2007, Accepted 22 May 2007. We thank Mary Y. Ryan for help with oocytes and molecular biology. This work was supported by grants from the National Institutes of Health (GM079427 and NS34407).
Funders:
Funding AgencyGrant Number
NIHGM079427
NIHNS34407
Issue or Number:7
PubMed Central ID:PMC1965434
Record Number:CaltechAUTHORS:20170408-214441240
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170408-214441240
Official Citation:Vincent P. Santarelli, Amy L. Eastwood, Dennis A. Dougherty, Christopher A. Ahern, Richard Horn, Calcium Block of Single Sodium Channels: Role of a Pore-Lining Aromatic Residue, Biophysical Journal, Volume 93, Issue 7, 2007, Pages 2341-2349, ISSN 0006-3495, https://doi.org/10.1529/biophysj.107.106856. (http://www.sciencedirect.com/science/article/pii/S0006349507714893)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76411
Collection:CaltechAUTHORS
Deposited By: 1Science Import
Deposited On:31 Mar 2018 00:02
Last Modified:03 Oct 2019 17:00

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