Journal article
Allosteric α1-Adrenoreceptor Antagonism by the Conopeptide ρ-TIA
The Journal of biological chemistry, Vol.278(36), pp.34451-34457
09/05/2003
DOI: 10.1074/jbc.M305410200
PMID: 12824165
Abstract
A peptide contained in the venom of the predatory marine snail Conus tulipa, ρ-TIA, has previously been shown to possess α1-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 α1B-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 (Arg4). An alanine walk of ρ-TIA confirmed the importance of Arg4 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.
Details
- Title: Subtitle
- Allosteric α1-Adrenoreceptor Antagonism by the Conopeptide ρ-TIA
- Creators
- Iain A SharpeLinda ThomasMarion LoughnanLeonid MotinElka PalantDaniel E CrokerDianne AlewoodSonghai ChenRobert M GrahamPaul F AlewoodDavid J AdamsRichard J Lewis
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.278(36), pp.34451-34457
- DOI
- 10.1074/jbc.M305410200
- PMID
- 12824165
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Language
- English
- Date published
- 09/05/2003
- Academic Unit
- Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040394102771
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