RIC‐3: a nicotinic acetylcholine receptor chaperone

RIC‐3 is a transmembrane protein which acts as a molecular chaperone of nicotinic acetylcholine receptors (nAChRs). For some nAChR subtypes (such as homomeric α7 neuronal nAChRs), RIC‐3 is required for efficient receptor folding, assembly and functional expression. In contrast, for other nAChR subtypes (such as heteromeric α4β2 neuronal nAChRs) there have been reports that RIC‐3 can both enhance and reduce levels of functional expression. There is also evidence that RIC‐3 can modulate maturation of the closely related 5‐hydroxytryptamine (5‐HT) receptor (5‐HT 3 R). As with heteromeric nAChRs, apparently contradictory results have been reported for the influence of RIC‐3 on 5‐HT 3 R maturation in different expression systems. Recent evidence indicates that these differences in RIC‐3 chaperone activity may be influenced by the host cell, suggesting that other proteins may play an important role in modulating the effects of RIC‐3 as a chaperone. RIC‐3 was originally identified in the nematode Caenorhabditis elegans as the protein encoded by the gene ric‐3 ( r esistance to i nhibitors of c holinesterase) and has subsequently been cloned and characterized from mammalian and insect species. This review provides a brief history of RIC‐3; from the identification of the ric‐3 gene in C. elegans in 1995 to the more recent demonstration of its activity as a nAChR chaperone. British Journal of Pharmacology (2008) 153 , S177–S183; doi: 10.1038/sj.bjp.0707661 ; published online 4 February 2008