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Vol. 20, Issue 5, 1419-1427, March 1, 2009

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The Conserved RIC-3 Coiled-Coil Domain Mediates Receptor-specific Interactions with Nicotinic Acetylcholine Receptors

Yoav Biala^*, Jana F. Liewald, Hagit Cohen Ben-Ami^*, Alexander Gottschalk^,, and Millet Treinin^*

*Department of Physiology, Hebrew University, Hadassah Medical School, Jerusalem, 91120, Israel; and Department of Biochemistry, Chemistry and Pharmacy, Institute of Biochemistry, Biocenter N210/220 and Cluster of Excellence Frankfurt-Macromolecular Complexes (CEF-MC), Johann Wolfgang Goethe-University Frankfurt, D-60438 Frankfurt, Germany

Submitted August 19, 2008; Revised November 25, 2008; Accepted December 22, 2008
Monitoring Editor: Reid Gilmore

RIC-3 belongs to a conserved family of proteins influencing nicotinic acetylcholine receptor (nAChR) maturation. RIC-3 proteins are integral membrane proteins residing in the endoplasmic reticulum (ER), and containing a C-terminal coiled-coil domain (CC-I). Conservation of CC-I in all RIC-3 family members indicates its importance; however, previous studies could not show its function. To examine the role of CC-I, we studied effects of its deletion on Caenorhabditis elegans nAChRs in vivo. Presence of CC-I promoted maturation of particular nAChRs expressed in body-wall muscle, whereas it was not required for other nAChR subtypes expressed in neurons or pharyngeal muscles. This effect is receptor-specific, because it could be reproduced after heterologous expression. Consistently, coimmunoprecipitation analysis showed that CC-I enhances the interaction of RIC-3 with a nAChR that requires CC-I in vivo; thus CC-I appears to enhance affinity of RIC-3 to specific nAChRs. However, we found that this function of CC-I is redundant with functions of sequences downstream to CC-I, potentially a second coiled-coil. Alternative splicing in both vertebrates and invertebrates generates RIC-3 transcripts that lack the entire C-terminus, or only CC-I. Thus, our results suggest that RIC-3 alternative splicing enables subtype specific regulation of nAChR maturation.

Address correspondence to: Millet Treinin (millet_t{at}cc.huji.ac.il)

Abbreviations used: nAChR, nicotinic acetylcholine receptor; ER, endoplasmic reticulum.

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