Publication Date:
2009-03-03
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755585/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755585/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xiu, Xinan -- Puskar, Nyssa L -- Shanata, Jai A P -- Lester, Henry A -- Dougherty, Dennis A -- NS 11756/NS/NINDS NIH HHS/ -- NS 34407/NS/NINDS NIH HHS/ -- R01 DA017279/DA/NIDA NIH HHS/ -- R01 NS011756/NS/NINDS NIH HHS/ -- R01 NS011756-33/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Mar 26;458(7237):534-7. doi: 10.1038/nature07768. Epub 2009 Mar 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19252481" target="_blank"〉PubMed〈/a〉
Keywords:
Acetylcholine/chemistry/metabolism
;
Animals
;
Binding Sites
;
Brain/*metabolism
;
Cations/metabolism
;
Halogenation
;
Mice
;
Models, Molecular
;
Nicotine/chemistry/*metabolism
;
Nicotinic Agonists/metabolism
;
Oocytes/metabolism
;
Organ Specificity
;
Protein Binding
;
Protein Conformation
;
Rats
;
Receptors, Nicotinic/chemistry/genetics/*metabolism
;
Smoking/adverse effects
;
Substance-Related Disorders/metabolism
;
Tryptophan/chemistry/metabolism
;
Xenopus laevis
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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