from a conformational change of the receptors that makes their degradation and removal from the cell surface slower (Peng et al., 1994). Another possible mechanism is an increase in receptor trafficking to the cell surface upon long exposures to nicotine (Harkness and Millar, 2002). An increase in the intracellular receptor pool caused by enhanced receptor assembly and/or maturation of the subunits in the endoplasmic reticulum has also been proposed (Nashmi et al., 2003). Additionally, nicotine can reportedly facilitate receptor maturation by acting as a chaperone in the endoplasmic reticulum (Nashmi et al., 2003; Srinivasan et al., 2011). However, membrane-impermanent ligands can also induce up-regulation of surface receptors; therefore, second messengers must exist that are sufficient to drive this response (Whiteaker et al., 1998; Darsow et al., 2005). In order for nicotine-induced up-regulation to occur, nAChRs must pass through the secretory pathway before being inserted into the membrane (Darsow et al., 2005) suggesting that up-regulation is not due to stabilization of nAChRs in the plasma membrane.
