The Function of AdTx1 for α1A-adrenoceptor

2018-08-18

Introduction 

AdTx1, also called as ρ-Da1a, is a polypeptide of 65 amino acids stabilized by four disulfide bonds, which has a strong affinity for the G-protein-coupled α1A-adrenoceptor. Adrenoceptors are divided into three classes (α1, α2 and β), and a1-adrenoceptors were further divided into three subtypes (α1A, α1B and α1D). α1-adrenoceptors are involved in the regulation of uro-genital tissue muscle tone (α1A receptors), myocardial contractility (α1B receptors) and vascular tone (α1D receptors). AdTx1 is a three-finger fold toxin from green mamba venom, and it is the most specific and selective peptide inhibitor for the α1A-adrenoceptor identified to date.

Biological Activity

AdTx1 has atypical pharmacological properties, including incomplete inhibition of 3H-prazosin or 125I-HEAT binding and insurmountable antagonist action. The affinity (pKi 9.26) and selectivity of AdTx1 for the α1A-adrenoceptor were confirmed by comparing binding to human adrenoceptors expressed in eukaryotic cells. Equilibrium and kinetic binding experiments were used to demonstrate that AdTx1, prazosin and HEAT compete at the α1A-adrenoceptor. AdTx1 did not affect the dissociation kinetics of 3H-prazosin or 125I-HEAT, and the IC50 of AdTx1, determined by competition experiments, increased linearly with the concentration of radioligands used, while the residual binding by AdTx1 remained stable. The effect of AdTx1 on agonist-stimulated Ca2+ release was insurmountable in the presence of phenethylamine- or imidazoline-type agonists. Ten mutations in the orthosteric binding pocket of the α1A-adrenoceptor were evaluated for alterations in AdTx1 affinity.

Function

Toxins active on GPCR are only found in two venomous animals, Marine-cone snails and snakes. These toxins can display many pharmacological properties, such as agonists, antagonists or allosteric modulators. Animal venoms could be a novel source of new GPCRs ligands. Using a combination of liquid chromatography and binding experiments, researchers identified AdTx1 as the first peptide that shows high affinity and selectivity for human α1A-adrenoceptor subtype. Its peptidic nature can be exploited to develop new tools, and due to its potency and selectivity, AdTx1 is a new pharmacological tool, which could be useful to clarify the physiological functions of α1A-adrenoceptor in animal models. Moreover, this peptide could be the basis for the synthesis of new α1A-adrenoceptor antagonists that could be used to treat lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH).

References:

1. L Quinton, E Girard et al. Isolation and pharmacological characterization of AdTx1, a natural peptide displaying specific insurmountable antagonism of the α1A-adrenoceptor. British Journal of Pharmacology, 2010, 159, 316-325.

2. S Palea, A Maiga et al. Effects of ρ-Da1a a peptidic α1A-adrenoceptor antagonist in human isolated prostatic adenoma and anaesthetized rats. British Journal of Pharmacology, 2013, 168, 618-631.

3. Arhamatoulaye Maïga1, Jon Merlin et al. Orthosteric Binding of ρ-Da1a, a Natural Peptide of Snake Venom Interacting Selectively with the α1A-adrenoceptor. Plos One, 2013, 8 (7), e68841.

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