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Years of structural work and wider studies have finally culminated in an explanation for nicotine's overwhelming affinity for brain receptors and the addictive molecule's almost total disregard for the nicotine receptors found in muscle tissues. "Nicotine addiction begins with high-affinity binding of nicotine to acetylcholine (ACh) receptors in the brain," the researchers say, "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." The new research now provides intriguing clues as to the underlying chemical nature of addiction to tobacco and also offers an explanation as to why a single cigarette, despite nicotine's predicted toxicity does not kill a smoker immediately. Chemist Dennis Dougherty and biologist Henry Lester of the California Institute of Technology, in Pasadena, California, and colleagues have published a solution to what they describe as the chemical mystery of nicotine addiction in the journal Nature. Dougherty has pioneered studies of nicotine and its physiological effects as well as investigating how membrane-bound proteins interact with this, and other small molecules. The researchers point out that if nicotine were to activate its receptors in muscle tissue as potently as it does in the brain, smoking would trigger intolerable and potentially lethal muscle contractions. This discrimination between the effects of nicotine on brain and muscle has puzzled biomedical researchers for years. Now, Dougherty and his team believe the explanation lies in how a specific interaction between nicotine and its receptor takes place. Their structural studies, which combine organic synthesis, molecular biology, electrophysiology, and computer modelling, can reveal how changes in amino acids might affect the affinity of a given protein for a particular substrate. In 2005, Dougherty and his colleagues looked at the binding of three distinct agonists -acetylcholine (ACh), nicotine, and epibatidine - to the nicotinic acetylcholine receptor using unnatural amino acid mutagenesis as a demonstrator for what might be possible. This earlier study, among several others over the last decade, illustrate the complexities of the interactions between substrates (often drug molecules) and membrane receptors and established a paradigm for obtaining detailed structural information. They have now used their expertise in this area to switch amino acids in the receptor and to show that the positive charge on the nicotine molecule has an affinity for a specific aromatic amino acid, tryptophan, in the box region of the receptor found in the brain. Although the receptor found in muscle tissue is broadly similar this so-called "cation-pi" interaction does not occur in muscle because there is a subtle difference between the binding pockets in each receptor, the lysine is missing and a glycine takes its place in the receptor box region. "TrpB makes a cation-pi interaction to the positive charge of nicotine in the brain receptor; but this strong binding interaction is absent in the muscle receptor," Dougherty told SpectroscopyNOW. "The lysine of interest is a bit remote to the binding site, but it influences the shape of the binding site so the nicotine can cosy up to TrpB." Ion channels and neuroreceptors, of which the nicotine receptor is just one example, are integral membrane proteins involved in memory, learning, and sensory perception. Learning how they behave will not only clarify our understanding of biology but could provide new targets for pharmaceuticals intended to treat Alzheimer's disease, Parkinson's disease, schizophrenia, learning and attention deficits, and many others disorders. In independent research published earlier this year, a team at Duke University revealed that there are different taste pathways for nicotine. This work might also lead to new insights into helping people quit smoking by providing a novel approach to smoking-cessation products. The team used genetic manipulation and measured neuronal activity in mice, which revealed how nicotine stimulates the brain's sensory systems via different pathways, in a manner analogous to the way we taste things. "We learned some of nicotine's secrets," explains Albino Oliveira-Maia. "This is the first study to explore both the peripheral taste pathways activated by nicotine, and how these pathways are integrated in sensory areas of the brain." Related links:
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