Nicotine And Up-Regulation

This article from Lehigh University explores a wide arrays of ways of how nicotine works with its up-regulation mechanisms from many angles. It is a lengthy article but it is worth the read. We have put a small intro below which should give you a good idea of what this study is really about and its tremendous implications.


Nicotine up-regulates alpha beta2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning

Nicotine And Upregulation


"Repeated or chronic exposure to nicotine—beyond the seconds and minutes that lead to receptor activation and/or desensitization—is essential for nicotine dependence (Kauer and Malenka, 2007; Kalivas et al., 2009; Koob, 2009). Chronic exposure also apparently underlies the inverse correlation between a person’s history of tobacco use and his or her susceptibility to Parkinson’s disease (Ritz et al., 2007). Literature since 1983 also shows that chronic nicotine increases the number of neuronal nicotinic acetylcholine receptors (nAChRs) (Marks et al., 1983; Schwartz and Kellar, 1983). nAChRs, a superfamily of ligand-gated ion channels, activated by acetylcholine and nicotine, assemble as homopentameric or heteropentameric complexes comprising various combinations of alpha (alpha2 to alpha10) and beta (beta2 to beta4) subunits (Gotti et al., 2006). Nicotine-induced “up-regulation” has been replicated many times in systems ranging from clonal cell lines to primary neurons in culture, to mouse models, and to smokers’ brains (Breese et al., 1997; Court et al., 1998; Staley et al., 2006; Mukhin et al., 2008; Albuquerque et al., 2009; Lester et al., 2009). Bronchial epithelium cells also express nAChRs, and these are also up-regulated by nicotine (Fu et al., 2009). One or more mechanisms common to all such cellular systems presumably govern up-regulation. Therefore, studies with mechanistically favorable heterologously expressed preparations, such as nAChRs in oocytes and clonal mammalian cell lines, have good relevance to the pathophysiology of chronic nicotine. Data from such favorable systems show that nicotine enhances the assembly of functional nAChRs containing the alpha4 and beta2 subunits and also causes the preferential assembly of receptors with (alpha4)2(beta2)3 stoichiometry (Buisson and Bertrand, 2001; Nelson et al., 2003; Kuryatov et al., 2005; Sallette et al., 2005; Vallejo et al., 2005; Son et al., 2009). Mechanisms proposed for the effect of nicotine on nAChR assembly include the idea that nicotine acts as a maturational enhancer (Sallette et al., 2005), a novel slow stabilizer (Vallejo et al., 2005), and/or a pharmacological chaperone of nAChRs (Kuryatov et al., 2005; Lester et al., 2009)."

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