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J. Biol. Chem., Vol. 276, Issue 35, 33001-33010, August 31, 2001
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From the Department of Physiology and Biophysics and the Department
of Pharmacology and Therapeutics, Neuroscience and Smooth Muscle
Research Groups, University of Calgary,
Calgary, Alberta T2N 4N1 , Canada
We have recently reported that transfer of the
domain IIS6 region from rapidly inactivating R-type
(
Identification of Inactivation Determinants in the
Domain IIS6 Region of High Voltage-activated Calcium Channels*
and
1E) calcium channels to slowly inactivating
L-type (1C) calcium channel confers rapid inactivation
(Stotz, S. C., Hamid, J., Spaetgens, R. L., Jarvis, S. E., and Zamponi, G. W. (2000) J. Biol.
Chem. 275, 24575-24582). Here we have identified individual
amino acid residues in the IIS6 regions that are responsible for these
effects. In this region, 1C and 1E
channels differ in seven residues, and exchanging five of those
residues individually or in combination did not significantly affect
inactivation kinetics. By contrast, replacement of residues
Phe-823 or Ile-829 of 1C with the corresponding
1E residues significantly accelerated inactivation
rates and, when substituted concomitantly, approached the rapid
inactivation kinetics of R-type channels. A systematic
substitution of these residues with a series of other amino
acids revealed that decreasing side chain size at position 823 accelerates inactivation, whereas a dependence of the
inactivation kinetics on the degree of hydrophobicity could be observed
at position 829. Although these point mutations facilitated rapid entry
into the inactivated state of the channel, they had little to no
effect on the rate of recovery from inactivation. This suggests that
the development of and recovery from inactivation are governed by
separate structural determinants. Finally, the effects of mutations
that accelerated 1C inactivation could still be
antagonized following coexpression of the rat 
2a subunit
or by domain I-II linker substitutions that produce ultra slow
inactivation of wild type channels, indicating that the inactivation
kinetics seen with the mutants remain subject to regulation by the
domain I-II linker. Overall, our results provide novel insights into a
complex process underlying calcium channel inactivation.
*
This work was supported in part by a grant from the Heart
and Stroke Foundation of Alberta and the Northwest Territories and the
Canadian Institutes of Health Research.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of studentship awards from the Alberta Heritage
Foundation for Medical Research, Canadian Institutes of Health
Research, and the University of Calgary.
§
Recipient of faculty scholarships from the Canadian Institutes of
Health Research, the Alberta Heritage Foundation for Medical Research,
and the EJLB Foundation and holds the Novartis Chair for
Schizophrenia Research. To whom correspondence should be addressed: Dept. of Physiology and Biophysics, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada. Tel.: 403-220-8687; Fax. 403-210-8106; E-mail: Zamponi@ucalgary.ca.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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