Cation−π Interactions in Ligand Recognition by Serotonergic (5-HT3A) and Nicotinic Acetylcholine Receptors: The Anomalous Binding Properties of Nicotine
Abstract
A series of tryptophan analogues has been introduced into the binding site regions of two ion channels, the ligand-gated nicotinic acetylcholine and serotonin 5-HT(3A) receptors, using unnatural amino acid mutagenesis and heterologous expression in Xenopus oocytes. A cation-pi interaction between serotonin and Trp183 of the serotonin channel 5-HT(3A)R is identified for the first time, precisely locating the ligand-binding site of this receptor. The energetic contribution of the observed cation-pi interaction between a tryptophan and the primary ammonium ion of serotonin is estimated to be approximately 4 kcal/mol, while the comparable interaction with the quaternary ammonium of acetylcholine is approximately 2 kcal/mol. The binding mode of nicotine to the nicotinic receptor of mouse muscle is examined by the same technique and found to differ significantly from that of the natural agonist, acetylcholine.
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The EC50 for nicotine at (α4)2(β2)3 neuronal receptors is ~1 μM; at (α1)2β1γδ muscle receptors, ~400 μM.
“The EC50 for nicotine at (α4)2(β2)3 neuronal receptors is ~1 μM; at (α1)2β1γδ muscle receptors, ~ 400 μM.”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [45]
Nicotine makes neither the cation-π nor the hydrogen-bond interaction with the muscle receptor.
“Nicotine makes neither interaction with the muscle receptor (45,46).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [45]
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- Authors
- Beene, D. L., Brandt, G. S., Zhong, W., Zacharias, N. M., Lester, H. A., & Dougherty, D. A.
- Affiliations
- California Institute of Technology (US)
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2002-07-19
- Volume
- 41
- Issue
- 32
- Pages
- 10262-10269
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2004976660
- Cited by
- 300
- References
- 18
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 10 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 12 · 2019: 11 · 2018: 9 · 2017: 7 · 2016: 10 · 2015: 16 · 2014: 11 · 2013: 14 · 2012: 22
- FWCI
- 6.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS34407, NS 11756, R01NS011756)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- cation-π interactions, 5-HT3A receptor, nicotinic acetylcholine receptors, nicotine binding, serotonin binding, tryptophan analogues, ligand-gated ion channels, ligand recognition, unnatural amino acid mutagenesis, ligand binding sites, acetylcholine binding, quaternary ammonium compounds
- MeSH terms
- Alkylation, Amino Acid Sequence, Animals, Binding Sites, Cations, Dose-Response Relationship, Drug, Female, Fluorine Radioisotopes, Ligands, Molecular Sequence Data, Nicotine, Pyridinium Compounds, Receptors, Nicotinic, Receptors, Serotonin, Serotonin, Tryptophan, Xenopus laevis, Mutagenesis, Site-Directed, Serotonin Receptor Agonists, Patch-Clamp Techniques, Amino Acid Substitution, Receptors, Serotonin, 5-HT3, Mice, Static Electricity
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