© 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
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