The DOI matches its Crossref record; 31 of the 32 references it cites were found in a registry or an index.
Nicotine binding to brain receptors requires a strong cation–π interaction
Open accessAbstract
Nicotine addiction begins with high-affinity binding of nicotine to acetylcholine (ACh) receptors in the brain. The end result is over 4,000,000 smoking-related deaths annually worldwide and the largest source of preventable mortality in developed countries. Stress reduction, pleasure, improved cognition and other central nervous system effects are strongly associated with smoking. However, if nicotine activated ACh receptors found in muscle as potently as it does brain ACh receptors, smoking would cause intolerable and perhaps fatal muscle contractions. Despite extensive pharmacological, functional and structural studies of ACh receptors, the basis for the differential action of nicotine on brain compared with muscle ACh receptors has not been determined. Here we show that at the alpha4beta2 brain receptors thought to underlie nicotine addiction, the high affinity for nicotine is the result of a strong cation-pi interaction to a specific aromatic amino acid of the receptor, TrpB. In contrast, the low affinity for nicotine at the muscle-type ACh receptor is largely due to the fact that this key interaction is absent, even though the immediate binding site residues, including the key amino acid TrpB, are identical in the brain and muscle receptors. At the same time a hydrogen bond from nicotine to the backbone carbonyl of TrpB is enhanced in the neuronal receptor relative to the muscle type. A point mutation near TrpB that differentiates alpha4beta2 and muscle-type receptors seems to influence the shape of the binding site, allowing nicotine to interact more strongly with TrpB in the neuronal receptor. ACh receptors are established therapeutic targets for Alzheimer's disease, schizophrenia, Parkinson's disease, smoking cessation, pain, attention-deficit hyperactivity disorder, epilepsy, autism and depression. Along with solving a chemical mystery in nicotine addiction, our results provide guidance for efforts to develop drugs that target specific types of nicotinic receptors.
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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.”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [44]
In the citing paper
“This difference arises because nicotine makes a cation-π interaction with a Trp residue in loop B of the α4 subunit, and a hydrogen bond with the backbone carbonyl group of the peptide bond between this residue and the adjacent downstream residue (44).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [44]
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Cites
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors
Brejc, K., van Dijk, W. J., Klaassen, R. V., Schuurmans, M., John van der, O. O. S. T., Smit, A. B., & Sixma, T. K. (2001) · Nature · doi:10.1038/35077011 · Cited by 1,761
Varenicline: An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation
Coe, J. W., Brooks, P. R., Vetelino, M. G., Wirtz, M. C., Arnold, E. P., Huang, J., Sands, S. B., Davis, T. I., Lebel, L. A., Fox, C. B., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050069n · Cited by 930
Brain nicotinic acetylcholine receptors: native subtypes and their relevance
Gotti, C., Zoli, M., & Clementi, F. (2006) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2006.07.004 · Cited by 882
Nicotinic Receptors at the Amino Acid Level
Corringer, P., Novère, N. G. L., & Changeux, J. (2000) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.40.1.431 · Cited by 832
Celie, P. H. N., van Rossum-Fikkert, S. E., van Dijk, W. J., Brejc, K., Smit, A. B., & Sixma, T. K. (2004) · Neuron · doi:10.1016/s0896-6273(04)00115-1 · Cited by 781
Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas
Mansvelder, H. D., Keath, J. R., & McGehee, D. S. (2002) · Neuron · doi:10.1016/s0896-6273(02)00625-6 · Cited by 701
Nicotine Activation of α4* Receptors: Sufficient for Reward, Tolerance, and Sensitization
Tapper, A. R., McKinney, S. L., Nashmi, R., Schwarz, J., Deshpande, P., Labarca, C., Whiteaker, P., Marks, M. J., Collins, A. C., & Lester, H. A. (2004) · Science · doi:10.1126/science.1099420 · Cited by 686
Self-citationHansen, S. B., Sulzenbacher, G., Huxford, T., Marchot, P., Taylor, P., & Bourne, Y. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600828 · Cited by 649
Zhong, W., Gallivan, J. P., Zhang, Y., Li, L., Lester, H. A., & Dougherty, D. A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.21.12088 · Cited by 550
Self-citationAlternate stoichiometries of α4β2 nicotinic acetylcholine receptors
Nelson, M. E., Kuryatov, A., Choi, C. H., Zhou, Y., & Lindstrom, J. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.2.332 · Cited by 422
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Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality
Sletten, E. M., & Bertozzi, C. R. (2009) · Angewandte Chemie International Edition · doi:10.1002/anie.200900942 · Cited by 3,165
Aromatic Rings in Chemical and Biological Recognition: Energetics and Structures
Salonen, L. M., Ellermann, M., & Diederich, F. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201007560 · Cited by 1,542
Dougherty, D. A. (2012) · Accounts of Chemical Research · doi:10.1021/ar300265y · Cited by 1,160
Self-citationCation−π Interaction: Its Role and Relevance in Chemistry, Biology, and Material Science
Mahadevi, A. S., & Sastry, G. N. (2012) · Chemical Reviews · doi:10.1021/cr300222d · Cited by 1,158
Exploiting non-covalent π interactions for catalyst design
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Metadata
- Authors
- Xiu, X., Puskar, N. L., Shanata, J. A. P., Lester, H. A., & Dougherty, D. A.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Dougherty, Dennis A.
- Venue
- Nature
- Published
- 2009-03
- Volume
- 458
- Issue
- 7237
- Pages
- 534-537
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2755585
- OpenAlex
- W1483942114
- Cited by
- 363
- References
- 32
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 22 · 2023: 7 · 2022: 21 · 2021: 14 · 2020: 17 · 2019: 12 · 2018: 17 · 2017: 22 · 2016: 20 · 2015: 23 · 2014: 25 · 2013: 28 · 2012: 42
- FWCI
- 16.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Drug Abuse (R01DA017279)
- National Institute of Neurological Disorders and Stroke (NS34407, NS 11756, R01NS034407, R01NS011756, R37NS034407)
- 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
- nicotine, acetylcholine receptor, cation-π interactions, tryptophan residues, alpha4beta2 nicotinic receptor, receptor selectivity, hydrogen bonding, nicotine dependence, smoking cessation, nicotine analogues, receptor pharmacology, point mutations, receptor structure-function, smoking-related mortality, receptor desensitization, receptor internalization, receptor trafficking
- MeSH terms
- Acetylcholine, Animals, Binding Sites, Brain, Cations, Models, Molecular, Nicotine, Oocytes, Organ Specificity, Protein Binding, Protein Conformation, Receptors, Nicotinic, Smoking, Tryptophan, Xenopus laevis, Nicotinic Agonists, Substance-Related Disorders, Mice, Rats, Halogenation
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