ABSTRACT
Ion channels are complexly folded and assembled multipass transmembrane proteins that undergo biogenesis in the endoplasmic reticulum (ER) and traffic through the secretory pathway to the cell surface (1-3). Folding and assembly of the domains and subunits of ion channels take place in the ER and involve addition of disulfide bonds and conjugation of oligosaccharides that ultimately influence the correct conformation required to maintain the physical characteristics of the ion channel (4,5). Assembly of accessory subunits and modifications such as glycosylation, myristylation, and phosphorylation further modify the polypeptide backbone conformation and influence the activation and opening and closing characteristics of the channel. A cellular ‘‘quality control’’ is involved in detecting whether the ion channel is appropriately folded and assembled in the ER and is thought to operate by detecting exposed sequence and structural features in the protein (6). As the channel folds and assembles, these structural features are sterically occluded, buried within the polypeptide chains of the channel, and are no longer exposed to the cellular machinery that is involved in sequestering the channel in the ER (6-9). Forward directing targeting signals also appear to be present in ion channels and mightbecome exposed and accessible to the forward-targeting machinery when the channel is fully folded and assembled (10,11). Presumably, as the chan-
nel folds and assembles, the signals involved in sequestering are buried and those involved in forward targeting become exposed to the trafficking machinery that directs proteins upstream in the secretory pathway (12,13).
