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Originally published In Press as doi:10.1074/jbc.M100406200 on February 2, 2001

J. Biol. Chem., Vol. 276, Issue 19, 15728-15735, May 11, 2001
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Residue Gly1326 of the N-type Calcium Channel alpha 1B Subunit Controls Reversibility of omega -Conotoxin GVIA and MVIIA Block*

Zhong-Ping FengDagger §||, Jawed HamidDagger , Clinton DoeringDagger §, Gregory M. Bosey**, Terrance P. Snutch**Dagger Dagger , and Gerald W. ZamponiDagger §§

From the Dagger  Departments of Physiology & Biophysics and Pharmacology & Therapeutics, Neuroscience Research Group, University of Calgary, Calgary, Alberta T2N 4N1, Canada, § NeuroMed Technologies Inc., Vancouver V6T 1Z4, Canada, and the ** Biotechnology Laboratory, University of British Columbia, Vancouver V6T 1Z3, Canada

We recently reported that amino acid residues contained within a putative EF hand motif in the domain III S5-H5 region of the alpha 1B subunit affected the relative barium:calcium permeability of N-type calcium channels (Feng, Z. P., Hamid, J., Doering, C., Jarvis, S. E., Bosey, G. M., Bourinet, E., Snutch, T. P., and Zamponi, G. W. (2001) J. Biol. Chem. 276, 5726-5730). Since this region partially overlaps with residues previously implicated in block of the channel by omega -conotoxin GVIA, we assessed the effects of mutations in the putative EF hand domain on channel block by omega -conotoxin GVIA and the structurally related omega -conotoxin MVIIA. Both of the toxins irreversibly block the activity of wild type alpha 1B N-type channels. We find that in addition to previously identified amino acid residues, residues in positions 1326 and 1332 are important determinants of omega -conotoxin GVIA blockade. Substitution of residue Glu1332 to arginine slows the time course of development of block. Point mutations in position Gly1326 to either arginine, glutamic acid, or proline dramatically decrease the time constant for development of the block. Additionally, in the G1326P mutant channel activity was almost completely recovered following washout. A qualitatively similar result was obtained with omega -conotoxin MVIIA, suggesting that common molecular determinants underlie block by these two toxins. Taken together the data suggest that residue Gly1326 may form a barrier, which controls the access of peptide toxins to their blocking site within the outer vestibule of the channel pore and also stabilizes the toxin-channel interaction.

* This work was supported by operating grants (to G. W. Z.) from the Canadian Institutes of Health Research (CIHR) and the Heart and Stroke Foundation of Alberta and the Northwest Territories and through a Scholarship Award (to G. W. Z.) from the EJLB Foundation.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.

These authors contributed equally to this study.

|| Recipient of a postdoctoral fellowship from the Natural Science and Engineering Research Council of Canada.

Dagger Dagger Holds CIHR operating funds and a Senior Scientist award from the CIHR.

§§ Holds Faculty Scholarships from the Alberta Heritage Foundation for Medical Research (AHFMR) and the CIHR and is the Novartis Investigator in 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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