Nicotine Addiction
Nature 458, 534-537 (26 March 2009)
Nicotine binding to brain receptors requires a strong cation–
interaction
Xinan Xiu, Nyssa L. Puskar, Jai A. P. Shanata, Henry A. Lester & Dennis A. Dougherty
Divisions of Chemistry and Chemical Engineering and Biology
California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA
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 
4
2 brain receptors thought to underlie nicotine addiction, the high affinity for nicotine is the result of a strong cation–
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 42 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.
Nicotinic acetylcholine receptors (nAChRs) comprise a family of 
20 homologous subtypes that mediate fast synaptic transmission throughout the central and peripheral nervous systems. The neuronal receptors are found in the central nervous system (CNS) and autonomic ganglia. Of these, the subtype most strongly associated with nicotine addiction and the target of recently developed smoking cessation drugs is termed 42. The high nicotine affinity of 42 receptors, when combined with the ability of nicotine to cross the blood–brain barrier and its favourable pharmacokinetics, allows nicotine at the submicromolar concentrations in tobacco smoke to activate acutely these receptors, providing reward, cognitive sensitization and perhaps other effects. In addition, the high-affinity interaction allows smoked nicotine to act as an intracellular pharmacological chaperone of 42 receptors, leading to the upregulation of receptors thought to underlie effects of chronic exposure.
