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Proc Natl Acad Sci U S A
1995 Dec 05;9225:11839-43.
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Molecular determinants of drug access to the receptor site for antiarrhythmic drugs in the cardiac Na+ channel.
Qu Y
,
Rogers J
,
Tanada T
,
Scheuer T
,
Catterall WA
.
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The clinical efficacy of local anesthetic and antiarrhythmic drugs is due to their voltage- and frequency-dependent block of Na+ channels. Quaternary local anesthetic analogs such as QX-314, which are permanently charged and membrane-impermeant, effectively block cardiac Na+ channels when applied from either side of the membrane but block neuronal Na+ channels only from the intracellular side. This difference in extracellular access to QX-314 is retained when rat brain rIIA Na+ channel alpha subunits and rat heartrH1 Na+ channel alpha subunits are expressed transiently in tsA-201 cells. Amino acid residues in transmembrane segment S6 of homologous domain IV (IVS6) of Na+ channel alpha subunits have important effects on block by local anesthetic drugs. Although five amino acid residues in IVS6 differ between brain rIIA and cardiac rH1, exchange of these amino acid residues by site-directed mutagenesis showed that only conversion of Thr-1755 in rH1 to Val as in rIIA was sufficient to reduce the rate and extent of block by extracellular QX-314 and slow the escape of drug from closed channels after use-dependent block. Tetrodotoxin also reduced the rate of block by extracellular QX-314 and slowed escape of bound QX-314 via the extracellular pathway in rH1, indicating that QX-314 must move through the pore to escape. QX-314 binding was inhibited by mutation of Phe-1762 in the local anesthetic receptor site of rH1 to Ala whether the drug was applied extracellularly or intracellularly. Thus, QX-314 binds to a single site in the rH1 Na+ channel alpha subunit that contains Phe-1762, whether it is applied from the extracellular or intracellular side of the membrane. Access to that site from the extracellular side of the pore is determined by the amino acid at position 1755 in the rH1 cardiac Na+ channel.
Alpert,
Is there a second external lidocaine binding site on mammalian cardiac cells?
1989, Pubmed
Alpert,
Is there a second external lidocaine binding site on mammalian cardiac cells?
1989,
Pubmed
Auld,
A rat brain Na+ channel alpha subunit with novel gating properties.
1988,
Pubmed
,
Xenbase
Auld,
A neutral amino acid change in segment IIS4 dramatically alters the gating properties of the voltage-dependent sodium channel.
1990,
Pubmed
,
Xenbase
Backx,
Molecular localization of an ion-binding site within the pore of mammalian sodium channels.
1992,
Pubmed
Baumgarten,
External site for local anesthetic block of cardiac Na+ channels.
1991,
Pubmed
Butterworth,
Molecular mechanisms of local anesthesia: a review.
1990,
Pubmed
Cahalan,
Local anesthetic block of sodium channels in normal and pronase-treated squid giant axons.
1978,
Pubmed
Catterall,
Cellular and molecular biology of voltage-gated sodium channels.
1992,
Pubmed
Chahine,
Functional expression and properties of the human skeletal muscle sodium channel.
1994,
Pubmed
,
Xenbase
Cohen,
Voltage-dependent sodium channels.
1993,
Pubmed
Cribbs,
Functional expression of the rat heart I Na+ channel isoform. Demonstration of properties characteristic of native cardiac Na+ channels.
1990,
Pubmed
,
Xenbase
Frazier,
The site of action and active form of local anesthetics. II. Experiments with quaternary compounds.
1970,
Pubmed
Friel,
Dual control by ATP and acetylcholine of inwardly rectifying K+ channels in bovine atrial cells.
1990,
Pubmed
Gingrich,
Ultra-deep blockade of Na+ channels by a quaternary ammonium ion: catalysis by a transition-intermediate state?
1993,
Pubmed
Gintant,
The influence of molecular form of local anesthetic-type antiarrhythmic agents on reduction of the maximum upstroke velocity of canine cardiac Purkinje fibers.
1983,
Pubmed
Hille,
The pH-dependent rate of action of local anesthetics on the node of Ranvier.
1977,
Pubmed
Jurman,
Visual identification of individual transfected cells for electrophysiology using antibody-coated beads.
1994,
Pubmed
Kallen,
Primary structure and expression of a sodium channel characteristic of denervated and immature rat skeletal muscle.
1990,
Pubmed
Krieg,
Functional messenger RNAs are produced by SP6 in vitro transcription of cloned cDNAs.
1984,
Pubmed
,
Xenbase
Kunkel,
Rapid and efficient site-specific mutagenesis without phenotypic selection.
1985,
Pubmed
Lipkind,
A structural model of the tetrodotoxin and saxitoxin binding site of the Na+ channel.
1994,
Pubmed
Margolskee,
Panning transfected cells for electrophysiological studies.
1993,
Pubmed
McPhee,
A mutation in segment IVS6 disrupts fast inactivation of sodium channels.
1994,
Pubmed
,
Xenbase
Qu,
Modulation of cardiac Na+ channels expressed in a mammalian cell line and in ventricular myocytes by protein kinase C.
1994,
Pubmed
Ragsdale,
Molecular determinants of state-dependent block of Na+ channels by local anesthetics.
1994,
Pubmed
,
Xenbase
Rogart,
Molecular cloning of a putative tetrodotoxin-resistant rat heart Na+ channel isoform.
1989,
Pubmed
Satin,
A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties.
1992,
Pubmed
,
Xenbase
Starmer,
A quantitative description of QX222 blockade of sodium channels in squid axons.
1986,
Pubmed
Terlau,
Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II.
1991,
Pubmed
,
Xenbase
White,
SkM2, a Na+ channel cDNA clone from denervated skeletal muscle, encodes a tetrodotoxin-insensitive Na+ channel.
1991,
Pubmed
,
Xenbase
Yeh,
Interactions of monovalent cations with sodium channels in squid axon. II. Modification of pharmacological inactivation gating.
1985,
Pubmed
Zamponi,
Fast lidocaine block of cardiac and skeletal muscle sodium channels: one site with two routes of access.
1993,
Pubmed
