Journal article
Calcium Block of Single Sodium Channels: Role of a Pore-Lining Aromatic Residue
Biophysical journal, Vol.93(7), pp.2341-2349
2007
DOI: 10.1529/biophysj.107.106856
PMCID: PMC1965434
PMID: 17545248
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.
Details
- Title: Subtitle
- Calcium Block of Single Sodium Channels: Role of a Pore-Lining Aromatic Residue
- Creators
- Vincent P Santarelli - Department of Molecular Physiology and Biophysics, Institute of Hyperexcitability, Jefferson Medical College, Philadelphia, PennsylvaniaAmy L Eastwood - Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CaliforniaDennis A Dougherty - Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CaliforniaChristopher A Ahern - Department of Molecular Physiology and Biophysics, Institute of Hyperexcitability, Jefferson Medical College, Philadelphia, PennsylvaniaRichard Horn - Department of Molecular Physiology and Biophysics, Institute of Hyperexcitability, Jefferson Medical College, Philadelphia, Pennsylvania
- Resource Type
- Journal article
- Publication Details
- Biophysical journal, Vol.93(7), pp.2341-2349
- Publisher
- Elsevier Inc
- DOI
- 10.1529/biophysj.107.106856
- PMID
- 17545248
- PMCID
- PMC1965434
- ISSN
- 0006-3495
- eISSN
- 1542-0086
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: GM079427, NS34407
- Language
- English
- Date published
- 2007
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984070871602771
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