RIS ID
106020
Abstract
A peptide contained in the venom of the predatory marine snail Conus tulipa, ρ-TIA, has previously been shown to possess α 1,-adrenoreceptor antagonist activity. Here, we further characterize its pharmacological activity as well as its structure-activity relationships. In the isolated rat vas deferens, ρ-TIA inhibited α1, -adrenoreceptor-mediated increases in cytosolic Ca2+ concentration that were triggered by norepinephrine, but did not affect presynaptic α2-adrenoreceptor-mediated responses. In radioligand binding assays using [125I]HEAT, ρ-TIA displayed slightly greater potency at the α1B, than at the α1A or α1D, subtypes. Moreover, although it did not affect the rate of association for [3H]prazosin binding to the α 1B-adrenoreceptor, the dissociation rate was increased, indicating non-competitive antagonism by ρ-TIA. N-terminally truncated analogs of ρ-TIA were less active than the full-length peptide, with a large decline in activity observed upon removal of the fourth residue of ρ-TIA (Arg 4). An alanine walk of ρ-TIA confirmed the importance of Arg 4 for activity and revealed a number of other residues clustered around Arg4 that contribute to the potency of ρ-TIA. The unique allosteric antagonism of ρ-TIA resulting from its interaction with receptor residues that constitute a binding site that is distinct from that of the classical competitive α1,-adrenoreceptor antagonists may allow the development of inhibitors that are highly subtype selective.
Publication Details
Sharpe, I. A., Thomas, L., Loughnan, M., Motin, L., Palant, E., Croker, D. E., Alewood, D., Chen, S., Graham, R. M., Alewood, P. F., Adams, D. J. & Lewis, R. J. (2003). Allosteric α1-adrenoreceptor antagonism by the conopeptide ρ-TIA. Journal of Biological Chemistry, 278 (36), 34451-34457.