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J Biol Chem, Vol. 274, Issue 14, 9409-9420, April 2, 1999
From the Institute of Molecular Pharmacology and Biophysics,
University of Cincinnati College of Medicine,
Cincinnati, Ohio 45267-0828 and ¶ Faculty of Pharmaceutical
Sciences, Kumamoto University, Kumamoto 862, Japan
Mutations in motif IVS5 and IVS6 of the human
cardiac calcium channel were made using homologous residues from the
rat brain sodium channel 2a. [3H]PN200-110 and
allosteric binding assays revealed that the dihydropyridine and
benzothiazepine receptor sites maintained normal coupling in the
chimeric mutant channels. Whole cell voltage clamp recording from
Xenopus oocytes showed a dramatically slowed inactivation and a complete loss of use-dependent block for mutations in
the cytoplasmic connecting link to IVS5 (HHT-5371) and in IVS5
transmembrane segment (HHT-5411) with both diltiazem and verapamil.
However, the use-dependent block by isradipine was retained
by these two mutants. For mutants HHT-5411 and HHT-5371, the residual
current appeared associated with a loss of voltage dependence in the
rate of inactivation indicating a destabilization of the inactivated state. Furthermore, both HHT-5371 and -5411 recovered from inactivation significantly faster after drug block than that of the wild type channel. Our data demonstrate that accelerated recovery of HHT-5371 and
HHT-5411 decreased accumulation of these channels in inactivation during pulse trains and suggest a close link between inactivation gating of the channel and use-dependent block by
phenylalkylamines and benzothiazepines and provide evidence of a
role for the transmembrane and cytoplasmic regions of IVS5 in the
use-dependent block by diltiazem and verapamil.
A Region in IVS5 of the Human Cardiac L-type Calcium Channel
Is Required for the Use-dependent Block by
Phenylalkylamines and Benzothiazepines
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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