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

Xiu, Xinan and Puskar, Nyssa L. and Shanata, Jai A. P. and Lester, Henry A. and Dougherty, Dennis A. (2009) Nicotine binding to brain receptors requires a strong cation–π interaction. Nature, 458 (7237). pp. 534-537. ISSN 0028-0836. PMCID PMC2755585. doi:10.1038/nature07768.

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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 α4β2 brain receptors thought to underlie nicotine addiction, the high affinity for nicotine is the result of a strong cation–π 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 α4β2 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.

Item Type:Article
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URLURL TypeDescription CentralArticle ReadCube access
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2009 Nature Publishing Group. Received 26 November 2008; Accepted 9 January 2009; Published online 1 March 2009. We thank B. N. Cohen for advice on single-channel recording and analysis. This work was supported by the NIH (NS 34407; NS 11756) and the California Tobacco-Related Disease Research Program of the University of California, grant number 16RT-0160. J.A.P.S. was partially supported by an NRSA training grant.
Funding AgencyGrant Number
NIHNS 34407
NIHNS 11756
California Tobacco-Related Disease Research Program16RT-0160
NIH Predoctoral FellowshipUNSPECIFIED
Subject Keywords:acetylcholine-receptors; ion channels; M2 domain; agonists; ACHBP; site; activation; tolerance; complexes; chemistry
Issue or Number:7237
PubMed Central ID:PMC2755585
Record Number:CaltechAUTHORS:20090422-090708342
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14041
Deposited By: Tony Diaz
Deposited On:30 Apr 2009 22:39
Last Modified:08 Nov 2021 22:42

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