ArticleMolecular pharmacology2010
Molecular determinants for competitive inhibition of alpha4beta2 nicotinic acetylcholine receptors.
Article in Molecular pharmacology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 49 citations in OpenAlex.
- Facile synthesis of pyrrolo[2,1-a]isoquinolines by domino reaction of 1-aroyl-3,4-dihydroisoquinolines with conjugated ketones, nitroalkenes and nitriles.Molecular diversity · 2021Article
- Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins.Frontiers in neuroscience · 2020Review
- Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine α4β2, Dopamine and Serotonin Transporters.Molecules (Basel, Switzerland) · 2019Article
- The fifth subunit of the (α4β2)British journal of pharmacology · 2018Article
- A strategic approach to [6,6]-bicyclic lactones: application towards the CD fragment of DHβE.Beilstein journal of organic chemistry · 2017Article
- Pharmacologically distinct nicotinic acetylcholine receptors drive efferent-mediated excitation in calyx-bearing vestibular afferents.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Acetylcholine induces GABA release onto rod bipolar cells through heteromeric nicotinic receptors expressed in A17 amacrine cells.Frontiers in cellular neuroscience · 2015Article
- Article
- Functional expression of α7-nicotinic acetylcholine receptors by muscle afferent neurons.Journal of neurophysiology · 2014Article
- Non-equivalent ligand selectivity of agonist sites in (α4β2)2α4 nicotinic acetylcholine receptors: a key determinant of agonist efficacy.The Journal of biological chemistry · 2014Article
- Synthesis and Pharmacological Evaluation of DHβE Analogues as Neuronal Nicotinic Acetylcholine Receptor Antagonists.ACS medicinal chemistry letters · 2014Article
- Leishmanicidal evaluation of tetrahydroprotoberberine and spirocyclic erythrina-alkaloids.Molecules (Basel, Switzerland) · 2014Article
- Erythrina mulungu alkaloids are potent inhibitors of neuronal nicotinic receptor currents in mammalian cells.PloS one · 2013Article
- Crystal structure of Lymnaea stagnalis AChBP complexed with the potent nAChR antagonist DHβE suggests a unique mode of antagonism.PloS one · 2012Article
- Additional acetylcholine (ACh) binding site at alpha4/alpha4 interface of (alpha4beta2)2alpha4 nicotinic receptor influences agonist sensitivity.The Journal of biological chemistry · 2011Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
The Erythrina alkaloids erysodine and dihydro-beta-erythroidine (DHbetaE) are potent and selective competitive inhibitors of alpha4beta2 nicotinic acetylcholine receptors (nAChRs), but little is known about the molecular determinants of the sensitivity of this receptor subtype to inhibition by this class of antagonists. We addressed this issue by examining the effects of DHbetaE and a range of aromatic Erythrina alkaloids on [(3)H]cytisine binding and receptor function in conjunction with homology models of the alpha4beta2 nAChR, mutagenesis, and functional assays. The lactone group of DHbetaE and a hydroxyl group at position C-16 in aromatic Erythrina alkaloids were identified as major determinants of potency, which was decreased when the conserved residue Tyr126 in loop A of the alpha4 subunit was substituted by alanine. Sensitivity to inhibition was also decreased by substituting the conserved aromatic residues alpha4Trp182 (loop B), alpha4Tyr230 (loop C), and beta2Trp82 (loop D) and the nonconserved beta2Thr84; however, only alpha4Trp182 was predicted to contact bound antagonist, suggesting alpha4Tyr230, beta2Trp82, and beta2Thr84 contribute allosterically to the closed state elicited by bound antagonist. In addition, homology modeling predicted strong ionic interactions between the ammonium center of the Erythrina alkaloids and beta2Asp196, leading to the uncapping of loop C. Consistent with this, beta2D196A abolished sensitivity to inhibition by DHbetaE or erysodine but not by epierythratidine, which is not predicted to form ionic bonds with beta2Asp196. This residue is not conserved in subunits that comprise nAChRs with low sensitivity to inhibition by DHbetaE or erysodine, which highlights beta2Asp196 as a major determinant of the receptor selectivity of Erythrina alkaloids.
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