Simulation of nicotine-induced nAChR up-regulation. The experimental data are explained by a pharmacological chaperoning and trafficking scheme based on FOLDEX (Wiseman et al., 2007) and on a model for ERES formation (Heinzer et al., 2008). (A) The SePhaChARNS 2.0 model for explaining target measures 1–6. The reactions numbered <20 are identical to those of Wiseman et al. (2007); FOLDEX has been simplified for the SePhaChARNS 2.0 model. The reaction steps in purple type are influenced by the M3–M4 trafficking mutations. The nAChRs in partially and fully folded ER compartments are shown with gradient fills to denote that only near-membrane molecules are visible in TIRFM. FOLDEX step 14 (involving a protein co-chaperone) is inactivated in the present model because we have little information about protein co-chaperones in the present context. Reactions numbered >20 are added for the SePhaChARNS 2.0 model, which includes post-ER events. The ERES0 population comprises ERES that are visible with Sec24D-mcherry but associated with other cargo molecules or that reside in ER regions not containing nAChRs. ExMach, unspecified export machinery; ERAPF, ER-associated partial folding; ERAD, ER-associated degradation. (B) The simulated course of up-regulation at the PM for the exemplar parameters. The simulation was allowed to reach steady state (at nicotine = 0.0033 µM) before the period indicated. At time zero, the nicotine concentration was jumped to 0.1 µM. A vertical line is shown at 48 h = 1.9 × 105 s, the time of the measurements; parameters were chosen based on this time point.
