A schematic representation of selective pharmacological chaperoning of nAChRs in response to chronic nicotine. (A) Nicotine interconverts within milliseconds between the protonated membrane-impermeant form and the neutral membrane-permeant form. The latter enters cells and enters the ER (red arrow). Here, the charged form pharmacologically chaperones nAChRs so that increased numbers exit toward the Golgi via the COPII pathway, eventually resulting in receptor up-regulation at the PM. Thus, pharmacological chaperoning by nicotine is thought to underlie the process of nAChR up-regulation by chronic nicotine. (B) This study finds that nicotine-mediated up-regulation also depends on the COPI machinery involved in ER to Golgi and Golgi to ER transport of nAChRs. One possible explanation for the COPI dependence is that nicotine enters additional organelles and binds more extensively than previously thought within the early exocytic pathway, shown by the additional red arrows leading to both COPI and COPII vesicles, ERGIC, and cis-Golgi. See also the animation, “Nicotine Up-regulates nAChRs”: http://www.jgp.org/cgi/content/full/jgp.201311102/DC2.