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Biophys J
2008 Dec 01;9511:5138-52. doi: 10.1529/biophysj.108.130518.
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Bupivacaine blocks N-type inactivating Kv channels in the open state: no allosteric effect on inactivation kinetics.
Nilsson J
,
Madeja M
,
Elinder F
,
Arhem P
.
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Local anesthetics bind to ion channels in a state-dependent manner. For noninactivating voltage-gated K channels the binding mainly occurs in the open state, while for voltage-gated inactivating Na channels it is assumed to occur mainly in inactivated states, leading to an allosterically caused increase in the inactivation probability, reflected in a negative shift of the steady-state inactivation curve, prolonged recovery from inactivation, and a frequency-dependent block. How local anesthetics bind to N-type inactivating K channels is less explored. In this study, we have compared bupivacaine effects on inactivating (Shaker and K(v)3.4) and noninactivating (Shaker-IR and K(v)3.2) channels, expressed in Xenopus oocytes. Bupivacaine was found to block these channels time-dependently without shifting the steady-state inactivation curve markedly, without a prolonged recovery from inactivation, and without a frequency-dependent block. An analysis, including computational testing of kinetic models, suggests binding to the channel mainly in the open state, with affinities close to those estimated for corresponding noninactivating channels (300 and 280 microM for Shaker and Shaker-IR, and 60 and 90 microM for K(v)3.4 and K(v)3.2). The similar magnitudes of K(d), as well as of blocking and unblocking rate constants for inactivating and noninactivating Shaker channels, most likely exclude allosteric interactions between the inactivation mechanism and the binding site. The relevance of these results for understanding the action of local anesthetics on Na channels is discussed.
Arhem,
Mechanisms of anesthesia: towards integrating network, cellular, and molecular level modeling.
2003, Pubmed
Arhem,
Mechanisms of anesthesia: towards integrating network, cellular, and molecular level modeling.
2003,
Pubmed
Arias,
Kvbeta1.3 reduces the degree of stereoselective bupivacaine block of Kv1.5 channels.
2007,
Pubmed
,
Xenbase
Armstrong,
A model for 4-aminopyridine action on K channels: similarities to tetraethylammonium ion action.
2001,
Pubmed
Bean,
Lidocaine block of cardiac sodium channels.
1983,
Pubmed
Bennett,
On the molecular nature of the lidocaine receptor of cardiac Na+ channels. Modification of block by alterations in the alpha-subunit III-IV interdomain.
1995,
Pubmed
,
Xenbase
Cahalan,
Local anesthetic block of sodium channels in normal and pronase-treated squid giant axons.
1978,
Pubmed
Chernoff,
Kinetic analysis of phasic inhibition of neuronal sodium currents by lidocaine and bupivacaine.
1990,
Pubmed
Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed
Elinder,
Localization of the extracellular end of the voltage sensor S4 in a potassium channel.
2001,
Pubmed
,
Xenbase
Elinder,
Divalent cation effects on the Shaker K channel suggest a pentapeptide sequence as determinant of functional surface charge density.
1998,
Pubmed
,
Xenbase
Elinder,
Mechanisms of the tetrahydroaminoacridine effect on action potential and ion currents in myelinated axons.
1991,
Pubmed
,
Xenbase
Friederich,
Local anaesthetic sensitivities of cloned HERG channels from human heart: comparison with HERG/MiRP1 and HERG/MiRP1 T8A.
2004,
Pubmed
González,
Effects of bupivacaine and a novel local anesthetic, IQB-9302, on human cardiac K+ channels.
2001,
Pubmed
Grant,
Block of wild-type and inactivation-deficient cardiac sodium channels IFM/QQQ stably expressed in mammalian cells.
2000,
Pubmed
Hille,
Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction.
1977,
Pubmed
Hondeghem,
Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels.
1977,
Pubmed
Jiang,
The open pore conformation of potassium channels.
2002,
Pubmed
Kamb,
Molecular characterization of Shaker, a Drosophila gene that encodes a potassium channel.
1987,
Pubmed
Lipka,
Differential effects of bupivacaine on cardiac K channels: role of channel inactivation and subunit composition in drug-channel interaction.
1998,
Pubmed
,
Xenbase
Liu,
Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations.
2002,
Pubmed
Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed
Luzhkov,
Computational modelling of the open-state Kv 1.5 ion channel block by bupivacaine.
2003,
Pubmed
Madeja,
A concentration-clamp system allowing two-electrode voltage-clamp investigations in oocytes of Xenopus laevis.
1991,
Pubmed
,
Xenbase
Nilsson,
Local anesthetic block of Kv channels: role of the S6 helix and the S5-S6 linker for bupivacaine action.
2003,
Pubmed
,
Xenbase
Nilsson,
Mechanisms of bupivacaine action on Na+ and K+ channels in myelinated axons of Xenopus laevis.
1998,
Pubmed
,
Xenbase
O'Leary,
Cocaine binds to a common site on open and inactivated human heart (Na(v)1.5) sodium channels.
2002,
Pubmed
,
Xenbase
O'Leary,
Evidence for a direct interaction between internal tetra-alkylammonium cations and the inactivation gate of cardiac sodium channels.
1994,
Pubmed
Ragsdale,
Molecular determinants of state-dependent block of Na+ channels by local anesthetics.
1994,
Pubmed
,
Xenbase
Ramos,
State-dependent trapping of flecainide in the cardiac sodium channel.
2004,
Pubmed
,
Xenbase
Sanguinetti,
hERG potassium channels and cardiac arrhythmia.
2006,
Pubmed
Scheuer,
Commentary: A revised view of local anesthetic action: what channel state is really stabilized?
1999,
Pubmed
Starmer,
Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics.
1984,
Pubmed
Stephens,
Studies on the blocking action of human Kv3.4 inactivation peptide variants in the mouse cloned Kv1.1 K+ channel.
1996,
Pubmed
Stühmer,
Potassium channels expressed from rat brain cDNA have delayed rectifier properties.
1988,
Pubmed
,
Xenbase
Takahashi,
Mexiletine block of disease-associated mutations in S6 segments of the human skeletal muscle Na(+) channel.
2001,
Pubmed
Tempel,
Sequence of a probable potassium channel component encoded at Shaker locus of Drosophila.
1987,
Pubmed
Vedantham,
The position of the fast-inactivation gate during lidocaine block of voltage-gated Na+ channels.
1999,
Pubmed
,
Xenbase
Visan,
Mapping of maurotoxin binding sites on hKv1.2, hKv1.3, and hIKCa1 channels.
2004,
Pubmed
Wang,
Mexiletine block of wild-type and inactivation-deficient human skeletal muscle hNav1.4 Na+ channels.
2004,
Pubmed
Wang,
Block of inactivation-deficient Na+ channels by local anesthetics in stably transfected mammalian cells: evidence for drug binding along the activation pathway.
2004,
Pubmed
Wang,
State- and use-dependent block of muscle Nav1.4 and neuronal Nav1.7 voltage-gated Na+ channel isoforms by ranolazine.
2008,
Pubmed
Wang,
Inhibition of sodium currents by local anesthetics in chloramine-T-treated squid axons. The role of channel activation.
1987,
Pubmed
Wheeler,
The electrophysiologic actions of lidocaine and bupivacaine in the isolated, perfused canine heart.
1988,
Pubmed
Yang,
Inhibition of Na(+) current by imipramine and related compounds: different binding kinetics as an inactivation stabilizer and as an open channel blocker.
2002,
Pubmed
Yeh,
Sodium inactivation mechanism modulates QX-314 block of sodium channels in squid axons.
1978,
Pubmed
Zagotta,
Restoration of inactivation in mutants of Shaker potassium channels by a peptide derived from ShB.
1990,
Pubmed
,
Xenbase
Zagotta,
Shaker potassium channel gating. III: Evaluation of kinetic models for activation.
1994,
Pubmed
,
Xenbase
Zhou,
Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors.
2001,
Pubmed
,
Xenbase