© 1995 American Heart Association, Inc.
Articles |
On the Molecular Nature of the Lidocaine Receptor of Cardiac Na+ Channels
Modification of Block by Alterations in the 
-Subunit III-IV Interdomain
From the Departments of Pharmacology and Medicine (P.B.B., C.V.), Vanderbilt University Medical School, Nashville, Tenn, and the Department of Biochemistry and Biophysics (L.-Q.C., R.G.K.), University of Pennsylvania School of Medicine, Philadelphia.
Correspondence to Paul B. Bennett, PhD, Department of Pharmacology, 560 MRBII, Vanderbilt University Medical School, Nashville, TN 37232.
Abstract The mechanism of inhibition of Na+
channels by lidocaine has been suggested to involve low-affinity
binding to rested states and high-affinity binding to the
inactivated state of the channel, implying either multiple
receptor sites or allosteric modulation of receptor affinity.
Alternatively, the lidocaine receptor may be guarded by the channel
gates. To test these distinct hypotheses, inhibition of Na+
channels by lidocaine was studied by voltage-clamp methods in both
native and heterologous expression systems. Native Na+
channels were studied in guinea pig ventricular myocytes,
and recombinant human heart Na+ channels were expressed in
Xenopus laevis oocytes. Fast inactivation was eliminated by
mutating three amino acids (isoleucine, phenylalanine, and methionine)
in the III-IV interdomain to glutamines or by enzymatic digestion with
-chymotrypsin. In channels with intact fast inactivation, lidocaine
block developed with a time constant of 589±42 ms (n=7) at membrane
potentials between -50 and +20 mV, as measured by use of twin pulse
protocols. The IC50 was 36±1.8 µmol/L. Control channels
inactivated within 20 ms, and slow inactivation developed
much later (time constant of slow inactivation, 6.2±0.36 s). The major
component of block developed long after activated and open
channels were no longer available for drug binding. Control channels
recovered fully from inactivation in <50 ms at -120 mV (time
constant, 11±0.5 ms; n=50). In 30 µmol/L lidocaine, 49±3% of the
current recovered with a second larger time constant of 398±46 ms
(n=5). After removal of fast inactivation, either enzymatically or by
mutagenesis, the channels were no longer blocked by 50 µmol/L
lidocaine (n=8). Much higher concentrations of lidocaine produced a
tonic block (IC50, 0.4±0.07 mmol/L; n=13) and time
dependence suggestive of open-channel block. The results indicate the
importance of inactivated state block by therapeutic
concentrations of lidocaine and suggest that the molecular site of
action is the structural region of the channel that is responsible for
inactivation.
Key Words: Na+ channels • Na+ currents • local anesthetics • antiarrhythmic drugs
This article has been cited by other articles:
 |
|
 |
|
  D. A. Hanck, E. Nikitina, M. M. McNulty, H. A. Fozzard, G. M. Lipkind, and M. F. Sheets Using Lidocaine and Benzocaine to Link Sodium Channel Molecular Conformations to State-Dependent Antiarrhythmic Drug Affinity Circ. Res., August 28, 2009; 105(5): 492 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Sheets and D. A. Hanck Outward stabilization of the S4 segments in domains III and IV enhances lidocaine block of sodium channels J. Physiol., July 1, 2007; 582(1): 317 - 334. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Clancy, Z. I. Zhu, and Y. Rudy Pharmacogenetics and anti-arrhythmic drug therapy: a theoretical investigation Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H66 - H75. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. M. Smith, S. M. Amagasu, J. Hembrador, S. Axt, R. Chang, T. Church, C. Gee, J. R. Jacobsen, T. Jenkins, E. Kaufman, et al. Evidence for a Multivalent Interaction of Symmetrical, N-Linked, Lidocaine Dimers with Voltage-Gated Na+ Channels Mol. Pharmacol., March 1, 2006; 69(3): 921 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Ulbricht Sodium Channel Inactivation: Molecular Determinants and Modulation Physiol Rev, October 1, 2005; 85(4): 1271 - 1301. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Fukuda, T. Nakajima, P. C Viswanathan, and J. R Balser Compound-specific Na+ channel pore conformational changes induced by local anaesthetics J. Physiol., April 1, 2005; 564(1): 21 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Tsang, R. G. Tsushima, G. F. Tomaselli, R. A. Li, and P. H. Backx A Multifunctional Aromatic Residue in the External Pore Vestibule of Na+ Channels Contributes to the Local Anesthetic Receptor Mol. Pharmacol., February 1, 2005; 67(2): 424 - 434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. McNulty and D. A. Hanck State-Dependent Mibefradil Block of Na+ Channels Mol. Pharmacol., December 1, 2004; 66(6): 1652 - 1661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-Y. Wang, J. Mitchell, E. Moczydlowski, and G. K. Wang Block of Inactivation-deficient Na+ Channels by Local Anesthetics in Stably Transfected Mammalian Cells: Evidence for Drug Binding Along the Activation Pathway J. Gen. Physiol., November 29, 2004; 124(6): 691 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. O'Leary, M. Digregorio, and M. Chahine Closing and Inactivation Potentiate the Cocaethylene Inhibition of Cardiac Sodium Channels by Distinct Mechanisms Mol. Pharmacol., December 1, 2003; 64(6): 1575 - 1585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-C. Yang and C.-C. Kuo Inhibition of Na+ Current by Imipramine and Related Compounds: Different Binding Kinetics as an Inactivation Stabilizer and as an Open Channel Blocker Mol. Pharmacol., November 1, 2002; 62(5): 1228 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M E O'Leary and M Chahine Cocaine binds to a common site on open and inactivated human heart (Nav1.5) sodium channels J. Physiol., June 15, 2002; 541(3): 701 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J T Kimbrough and K J Gingrich Quaternary ammonium block of mutant Na+ channels lacking inactivation: features of a transition-intermediate mechanism J. Physiol., November 15, 2000; 529(1): 93 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B.-H. Ong, G. F. Tomaselli, and J. R. Balser A Structural Rearrangement in the Sodium Channel Pore Linked to Slow Inactivation and Use Dependence J. Gen. Physiol., November 1, 2000; 116(5): 653 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Sheets, J. W. Kyle, and D. A. Hanck The Role of the Putative Inactivation Lid in Sodium Channel Gating Current Immobilization J. Gen. Physiol., May 1, 2000; 115(5): 609 - 620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Chen, B.-H. Ong, N. G Kambouris, E. Marban, G. F Tomaselli, and J. R Balser Lidocaine induces a slow inactivated state in rat skeletal muscle sodium channels J. Physiol., April 1, 2000; 524(1): 37 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ono, T. Kaku, N. Makita, A. Kitabatake, and M. Arita Selective Block of Late Currents in the Delta KPQ Na+ Channel Mutant by Pilsicainide and Lidocaine with Distinct Mechanisms Mol. Pharmacol., February 1, 2000; 57(2): 392 - 400. [Abstract] [Full Text]
|
|
|
|
|
|
F. Lehmann-Horn and K. Jurkat-Rott Voltage-Gated Ion Channels and Hereditary Disease Physiol Rev, October 1, 1999; 79(4): 1317 - 1372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Balser Structure and function of the cardiac sodium channels Cardiovasc Res, May 1, 1999; 42(2): 327 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Vedantham and S. C. Cannon The Position of the Fast-Inactivation Gate during Lidocaine Block of Voltage-gated Na+ Channels J. Gen. Physiol., January 1, 1999; 113(1): 7 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Scheuer Commentary: A Revised View of Local Anesthetic Action: What Channel State Is Really Stabilized? J. Gen. Physiol., January 1, 1999; 113(1): 3 - 6. [Full Text] [PDF]
|
|
|
|
|
|
H.-L. Li, A. Galue, L. Meadows, and D. S. Ragsdale A Molecular Basis for the Different Local Anesthetic Affinities of Resting Versus Open and Inactivated States of the Sodium Channel Mol. Pharmacol., January 1, 1999; 55(1): 134 - 141. [Abstract] [Full Text]
|
|
|
|
|
|
N. G Kambouris, L. A Hastings, S. Stepanovic, E. Marban, G. F Tomaselli, and J. R Balser Mechanistic link between lidocaine block and inactivation probed by outer pore mutations in the rat {micro}1 skeletal muscle sodium channel J. Physiol., November 1, 1998; 512(3): 693 - 705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Pu, J. R. Balser, and P. A. Boyden Lidocaine Action on Na+ Currents in Ventricular Myocytes From the Epicardial Border Zone of the Infarcted Heart Circ. Res., August 24, 1998; 83(4): 431 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Wang, C. Quan, and S.-Y. Wang Local Anesthetic Block of Batrachotoxin-Resistant Muscle Na+ Channels Mol. Pharmacol., August 1, 1998; 54(2): 389 - 396. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. L. Sah, R. G. Tsushima, and P. H. Backx Effects of local anesthetics on Na+ channels containing the equine hyperkalemic periodic paralysis mutation Am J Physiol Cell Physiol, August 1, 1998; 275(2): C389 - C400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-F. Xiao, S. N. Wright, G. K. Wang, J. P. Morgan, and A. Leaf Fatty acids suppress voltage-gated Na+ currents in HEK293t cells transfected with the alpha -subunit of the human cardiac Na+ channel PNAS, March 3, 1998; 95(5): 2680 - 2685. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Dumaine and G. E. Kirsch Mechanism of lidocaine block of late current in long Q-T mutant Na+ channels Am J Physiol Heart Circ Physiol, February 1, 1998; 274(2): H477 - H487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kellenberger, J. W. West, T. Scheuer, and W. A. Catterall Molecular Analysis of the Putative Inactivation Particle in the Inactivation Gate of Brain Type IIA Na+ Channels J. Gen. Physiol., May 1, 1997; 109(5): 589 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kellenberger, T. Scheuer, and W. A. Catterall Movement of the Na+ Channel Inactivation Gate during Inactivation J. Biol. Chem., November 29, 1996; 271(48): 30971 - 30979. [Abstract] [Full Text] [PDF]
|
|