Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Isoform-specific lidocaine block of sodium channels explained by differences in gating.
Nuss HB
,
Kambouris NG
,
Marbán E
,
Tomaselli GF
,
Balser JR
.
???displayArticle.abstract???
When depolarized from typical resting membrane potentials (V(rest) approximately -90 mV), cardiac sodium (Na) currents are more sensitive to local anesthetics than brain or skeletal muscle Na currents. When expressed in Xenopus oocytes, lidocaine block of hH1 (human cardiac) Na current greatly exceeded that of mu1 (rat skeletal muscle) at membrane potentials near V(rest), whereas hyperpolarization to -140 mV equalized block of the two isoforms. Because the isoform-specific tonic block roughly parallels the drug-free voltage dependence of channel availability, isoform differences in the voltage dependence of fast inactivation could underlie the differences in block. However, after a brief (50 ms) depolarizing pulse, recovery from lidocaine block is similar for the two isoforms despite marked kinetic differences in drug-free recovery, suggesting that differences in fast inactivation cannot entirely explain the isoform difference in lidocaine action. Given the strong coupling between fast inactivation and other gating processes linked to depolarization (activation, slow inactivation), we considered the possibility that isoform differences in lidocaine block are explained by differences in these other gating processes. In whole-cell recordings from HEK-293 cells, the voltage dependence of hH1 current activation was approximately 20 mV more negative than that of mu1. Because activation and closed-state inactivation are positively coupled, these differences in activation were sufficient to shift hH1 availability to more negative membrane potentials. A mutant channel with enhanced closed-state inactivation gating (mu1-R1441C) exhibited increased lidocaine sensitivity, emphasizing the importance of closed-state inactivation in lidocaine action. Moreover, when the depolarization was prolonged to 1 s, recovery from a "slow" inactivated state with intermediate kinetics (I(M)) was fourfold longer in hH1 than in mu1, and recovery from lidocaine block in hH1 was similarly delayed relative to mu1. We propose that gating processes coupled to fast inactivation (activation and slow inactivation) are the key determinants of isoform-specific local anesthetic action.
Adelman,
The effects of external potassium and long duration voltage conditioning on the amplitude of sodium currents in the giant axon of the squid, Loligo pealei.
1969, Pubmed
Adelman,
The effects of external potassium and long duration voltage conditioning on the amplitude of sodium currents in the giant axon of the squid, Loligo pealei.
1969,
Pubmed
Aldrich,
A reinterpretation of mammalian sodium channel gating based on single channel recording.
,
Pubmed
An,
Lidocaine block of LQT-3 mutant human Na+ channels.
1996,
Pubmed
Armstrong,
Inactivation of the sodium channel. II. Gating current experiments.
1977,
Pubmed
Armstrong,
Fast and slow steps in the activation of sodium channels.
1979,
Pubmed
Balser,
Local anesthetics as effectors of allosteric gating. Lidocaine effects on inactivation-deficient rat skeletal muscle Na channels.
1996,
Pubmed
,
Xenbase
Balser,
Functional consequences of lidocaine binding to slow-inactivated sodium channels.
1996,
Pubmed
,
Xenbase
Balser,
External pore residue mediates slow inactivation in mu 1 rat skeletal muscle sodium channels.
1996,
Pubmed
,
Xenbase
Bean,
Lidocaine block of cardiac sodium channels.
1983,
Pubmed
Bénitah,
Molecular dynamics of the sodium channel pore vary with gating: interactions between P-segment motions and inactivation.
1999,
Pubmed
,
Xenbase
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
Chahine,
Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation.
1994,
Pubmed
Chandler,
Slow changes in membrane permeability and long-lasting action potentials in axons perfused with fluoride solutions.
1970,
Pubmed
Chen,
A unique role for the S4 segment of domain 4 in the inactivation of sodium channels.
1996,
Pubmed
,
Xenbase
COLE,
Potassium ion current in the squid giant axon: dynamic characteristic.
1960,
Pubmed
Courtney,
Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA.
1975,
Pubmed
Dumaine,
Multiple mechanisms of Na+ channel--linked long-QT syndrome.
1996,
Pubmed
,
Xenbase
Fan,
Two human paramyotonia congenita mutations have opposite effects on lidocaine block of Na+ channels expressed in a mammalian cell line.
1996,
Pubmed
Featherstone,
Interaction between fast and slow inactivation in Skm1 sodium channels.
1996,
Pubmed
,
Xenbase
Hille,
Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction.
1977,
Pubmed
HODGKIN,
A quantitative description of membrane current and its application to conduction and excitation in nerve.
1952,
Pubmed
Hondeghem,
Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels.
1977,
Pubmed
Ji,
Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating.
1996,
Pubmed
Johns,
Suppression of neuronal and cardiac transient outward currents by viral gene transfer of dominant-negative Kv4.2 constructs.
1997,
Pubmed
Kambouris,
Mechanistic link between lidocaine block and inactivation probed by outer pore mutations in the rat micro1 skeletal muscle sodium channel.
1998,
Pubmed
,
Xenbase
Kuo,
Na+ channels must deactivate to recover from inactivation.
1994,
Pubmed
McDonald,
Use-dependent block of single sodium channels by lidocaine in guinea pig ventricular myocytes.
1989,
Pubmed
Nuss,
Functional association of the beta 1 subunit with human cardiac (hH1) and rat skeletal muscle (mu 1) sodium channel alpha subunits expressed in Xenopus oocytes.
1995,
Pubmed
,
Xenbase
Nuss,
Cardiac sodium channels (hH1) are intrinsically more sensitive to block by lidocaine than are skeletal muscle (mu 1) channels.
1995,
Pubmed
Nuss,
Coupling between fast and slow inactivation revealed by analysis of a point mutation (F1304Q) in mu 1 rat skeletal muscle sodium channels.
1996,
Pubmed
,
Xenbase
Richmond,
Slow inactivation in human cardiac sodium channels.
1998,
Pubmed
,
Xenbase
Rudy,
Slow inactivation of the sodium conductance in squid giant axons. Pronase resistance.
1978,
Pubmed
Townsend,
Effect of alkali metal cations on slow inactivation of cardiac Na+ channels.
1997,
Pubmed
,
Xenbase
Vedantham,
The position of the fast-inactivation gate during lidocaine block of voltage-gated Na+ channels.
1999,
Pubmed
,
Xenbase
Villanueva,
Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells.
1998,
Pubmed
Wang,
Pharmacological targeting of long QT mutant sodium channels.
1997,
Pubmed
Wang,
Inhibition of sodium currents by local anesthetics in chloramine-T-treated squid axons. The role of channel activation.
1987,
Pubmed
Wang,
Distinct local anesthetic affinities in Na+ channel subtypes.
1996,
Pubmed
Wang,
Comparison of heterologously expressed human cardiac and skeletal muscle sodium channels.
1996,
Pubmed
,
Xenbase
Wright,
Differences in steady-state inactivation between Na channel isoforms affect local anesthetic binding affinity.
1997,
Pubmed
Wright,
State-dependent cocaine block of sodium channel isoforms, chimeras, and channels coexpressed with the beta1 subunit.
1999,
Pubmed
Yang,
Evidence for voltage-dependent S4 movement in sodium channels.
1995,
Pubmed
Yang,
Molecular basis of charge movement in voltage-gated sodium channels.
1996,
Pubmed
Yeh,
Sodium inactivation mechanism modulates QX-314 block of sodium channels in squid axons.
1978,
Pubmed
Yeh,
Na channel activation gate modulates slow recovery from use-dependent block by local anesthetics in squid giant axons.
1985,
Pubmed
Zilberter,
Ca-sensitive slow inactivation and lidocaine-induced block of sodium channels in rat cardiac cells.
1991,
Pubmed
