The upregulation of α4β2∗ nAChRs by chronic nicotine treatment has been replicated many times in numerous systems—transfected cell lines, neurons in culture, brain slices, and smokers’ brains ( Albuquerque et al., 2009, Fu et al., 2009, Lester et al., 2009 and Srinivasan et al., 2011). Upregulation is not accompanied by an increase in nAChR subunit mRNA ( Marks et al., 1992 and Huang et al., 2007). Instead, the membrane-permeant nicotine molecule appears to act intracellularly, as a selective pharmacological chaperone of acetylcholine receptor and stoichiometry (SePhaChARNS) ( Kuryatov et al., 2005, Sallette et al., 2005 and Lester et al.,

2009). SePhaChARNS arises in part from the thermodynamics of pharmacological chaperoning: ligand binding, especially at

subunit interfaces, stabilizes AChRs during assembly and maturation, selleck and this stabilization is most pronounced for the highest-affinity nAChR subunit compositions (especially α4β2∗), stoichiometries, and functional states of nAChRs. Another general aspect of upregulation is its applicability to two functional states induced by nicotine at nAChRs—activation and desensitization (Figure 3). Smoked nicotine acts differently from ACh in three ways (Lester et al., 2009). (1) Acetylcholinesterase does not hydrolyze nicotine; therefore, nicotine remains near nAChRs thousands of times longer than ACh. (2) Nicotine efficiently permeates membranes; therefore, it accumulates within cells (Putney and Borzelleca, 1971 and Lester et al., 2009). (3) Nicotine activates α4β2 nAChRs ∼400-fold more effectively than it activates muscle-type

nAChRs, because of cation-π and H-bond interactions at the agonist binding site Y-27632 supplier (Xiu et al., 2009). These factors lead nicotine to activate and desensitize the basal and nicotine-upregulated L-NAME HCl nAChRs for prolonged periods (minutes to hours). Therefore, desensitization influences actions of exogenous nicotine more than of endogenous ACh. In summary, upregulation due to chronic nicotine can magnify either activation or desensitization by acute nicotine. While it has been debated whether the acute effects of nicotine arise from activation or from desensitization, in the contemporary view (Figure 3) (Picciotto et al., 2008) both are thought to occur at appropriate neurons and synapses. At first glance, nicotine addiction and Parkinson’s disease seem related only by the participation of neighboring dopaminergic neuron populations: the former involves dopamine release from VTA neurons, and the latter involves degeneration in the substantia nigra pars compacta. In fact, more than 50 studies document an inverse correlation between a person’s history of tobacco use and his/her risk of Parkinson’s disease (Ritz et al., 2007). The effect is remarkably large—roughly a factor of two—when one considers that it derives from retrospective epidemiological studies (Hernán et al., 2002). Some Parkinson’s disease cases (∼10%) are directly linked to genetic mutations.