Residue Gly1326 of the N-type Calcium Channel α1B Subunit Controls Reversibility of ω-Conotoxin GVIA and MVIIA Block*
By Zhong-Ping Feng, J. Hamid, C. Doering, G. M. Bosey, Terrance P. Snutch, G. Zamponi. Journal of Biological Chemistry, 2001
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We recently reported that amino acid residues contained within a putative EF hand motif in the domain III S5-H5 region of the α1B 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 ω-conotoxin GVIA, we assessed the effects of mutations in the putative EF hand domain on channel block by ω-conotoxin GVIA and the structurally related ω-conotoxin MVIIA. Both of the toxins irreversibly block the activity of wild type α1B N-type channels. We find that in addition to previously identified amino acid residues, residues in positions 1326 and 1332 are important determinants of ω-conotoxin GVIA blockade. Substitution of residue Glu1332 to arginine slows the time course of development of block. Point mutations in position Gly1326to 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 ω-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.
Subfields: Cellular and Molecular Neuroscience, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/2b30ca56c065abf0092d58fb3847d1f1c86a4b14
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Citations in the corpus
- The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential (2015, methodology): “…modification. v-Conotoxin GVIA is a small 27–amino acid peptide with a backbone that is constrained by three disulfide bonds and it can be physically lodged into the permeation pathway of the channel, thus acting as a pore blocker (Reynolds et al., 1986; Ellinor et al., 1994; Feng et al., 2001).”