Journal
MOLECULAR PHARMACOLOGY
Volume 68, Issue 5, Pages 1431-1438Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.105.017459
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Recent studies have shown that RIC-3, originally identified in Caenorhabditis elegans as the protein encoded by the gene resistance to inhibitors of cholinesterase (ric-3), can enhance functional expression of alpha 7 nicotinic acetylcholine receptors (nAChRs). In the present study, the influence of C. elegans and human RIC-3 upon multiple homomeric (alpha 7, alpha 8, and alpha 9) and heteromeric (alpha 3 beta 2, alpha 3 beta 4, alpha 4 beta 2, alpha 4 beta 4, and alpha 9 alpha 10) nAChR subtypes has been examined in transfected mammalian cells by radioligand binding and functional characterization. Coexpression of RIC-3 facilitates a dramatic enhancement of the ability of alpha 7 (and the closely related alpha 8 subunit) to generate functional nAChRs in otherwise nonpermissive mammalian cells. In contrast, coexpression of RIC-3 did not facilitate functional expression of either homomeric alpha 9 or heteromeric alpha 9 alpha 10 nAChRs in mammalian cell lines. It is noteworthy that whereas RIC-3 has been reported to cause a marked functional inhibition of heteromeric nAChRs such as alpha 3 beta 4 and alpha 4 beta 2 expressed in Xenopus laevis oocytes, RIC-3 significantly enhances levels of functional expression of these and other (alpha 3 beta 2 and alpha 4 beta 4) heteromeric nAChRs when expressed in mammalian cell lines. In addition, the interaction of multiple nAChR subunits (alpha 3, alpha 4, alpha 7, beta 2, and beta 4) with RIC-3 has been demonstrated by coimmunoprecipitation from metabolically labeled transfected cells. It is significant that coimmunoprecipitation experiments have provided evidence that RIC-3 associates with unassembled nAChR subunits, a finding that is consistent with previous suggestions that RIC-3 may act by enhancing the maturation (subunit folding and assembly) of nAChRs. We conclude that RIC-3 is an nAChR-associated protein that can enhance functional expression of multiple nAChR subtypes in transfected mammalian cells.
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