Allosteric alpha 1-adrenoreceptor antagonism by the conopeptide rho-TIA
Sharpe, Iain A., Thomas, Linda, Loughnan, Marion, Motin, Leonid, Palant, Elka, Croker, Daniel E., Alewood, Dianne, Chen, Songhai, Graham, Robert M., Alewood, Paul F., Adams, David J., and Lewis, Richard J. (2003) Allosteric alpha 1-adrenoreceptor antagonism by the conopeptide rho-TIA. Journal of Biological Chemistry, 278 (36). pp. 34451-34457.
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A peptide contained in the venom of the predatory marine snail Conus tulipa, rho-TIA, has previously been shown to possess alpha1-adrenoreceptor antagonist activity. Here, we further characterize its pharmacological activity as well as its structure-activity relationships. In the isolated rat vas deferens, rho-TIA inhibited alpha1-adrenoreceptor-mediated increases in cytosolic Ca2+ concentration that were triggered by norepinephrine, but did not affect presynaptic alpha2-adrenoreceptor-mediated responses. In radioligand binding assays using [125I]HEAT, rho-TIA displayed slightly greater potency at the alpha 1B than at the alpha 1A or alpha 1D subtypes. Moreover, although it did not affect the rate of association for [3H]prazosin binding to the alpha 1B-adrenoreceptor, the dissociation rate was increased, indicating non-competitive antagonism by rho-TIA. N-terminally truncated analogs of rho-TIA were less active than the full-length peptide, with a large decline in activity observed upon removal of the fourth residue of rho-TIA (Arg4). An alanine walk of rho-TIA confirmed the importance of Arg4 for activity and revealed a number of other residues clustered around Arg4 that contribute to the potency of rho-TIA. The unique allosteric antagonism of rho-TIA resulting from its interaction with receptor residues that constitute a binding site that is distinct from that of the classical competitive alpha1-adrenoreceptor antagonists may allow the development of inhibitors that are highly subtype selective.
|Item Type:||Article (Refereed Research - C1)|
© 2003 Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, Inc., Bethesda, MD, 20814. Reproduced with permission from American Society for Biochemistry and Molecular Biology.
|Keywords:||alanine/chemistry, allosteric site, amino acid sequence, animals, arginine/chemistry, binding sites, binding, competitive, COS cells, cell membrane/metabolism, cells, cultured, conotoxins/*chemistry/*metabolism, cystine/chemistry, dose-response relationship, drug, kinetics, male, microscopy, fluorescence, models, molecular, molecular sequence data, muscle, smooth/cytology, peptide biosynthesis, peptides/chemistry/metabolism, protein binding, protein conformation, protein structure, tertiary, Rats, Wistar, Receptors, Adrenergic, alpha-1/*antagonists & inhibitors/*chemistry, structure-activity relationship, time factors, vas deferens/metabolism|
|FoR Codes:||06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060104 Cell Metabolism @ 34%|
06 BIOLOGICAL SCIENCES > 0699 Other Biological Sciences @ 33%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060110 Receptors and Membrane Biology @ 33%
|Deposited On:||08 Sep 2006|
|Last Modified:||02 Nov 2012 08:41|
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