Table 1. Summary of inside-out and outside-in signaling during smoking.

	Outside-in: Activated nAChRs in the plasma membrane	Inside-out: Chaperoned nAChRs in the ER
Nominal cellular effects	Na+ and Ca2+ influx, increased neuronal excitability, calcium signaling, nAChR desensitization	Stabilization of α4β2 subunit combinations, increased nAChR in the plasma membrane, biased subunit composition
EC50 for effect	0.3 – 4 µMa (Buisson et al., 1996; Gopalakrishnan et al., 1997; Pacheco et al., 2001; Kuryatov et al., 2005)	30 nM (Kuryatov et al., 2005)
Fraction average activation for a typical smoking habitb	0.1	0.7
Hypothesized organismal effects	Sense of well-being, cognitive boost, appetite suppression, increased tolerance of stressful stimuli, suppression of withdrawal (Miwa et al., 2011; Naudé et al., 2015; Nees, 2015; Picciotto et al., 2015)	Early events of nicotine dependence (Govind et al., 2009; Henderson and Lester, 2015)
Timescale of organismal effects	Minutes	Days to weeks

^aDependent on subunit composition and assay.

^b1 cigarette/hour for 12 h leads to ∼100 nM sustained nicotine concentration.