Cited by 383Nicotinic Acetylcholine Receptors StudyReceptor Mechanisms and SignalingNeuroscience and Neuropharmacology Research

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Nicotine binding to brain receptors requires a strong cation–π interaction

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Xiu, Xinan, Puskar, Nyssa L., Shanata, Jai A. P., Lester, Henry A., Dougherty, Dennis A.·2009·Nature

DOI 10.1038/nature07768PMC PMC2755585

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Abstract

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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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.
ORCID: Shanata, Jai A. P.
Lester, Henry A.
Dougherty, Dennis A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2009-03
Volume: 458
Issue: 7237
Pages: 534-537
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature07768
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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Nicotine binding to brain receptors requires a strong cation–π interaction

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