8.A.71 The RIC3 Protein (RIC3) Family The resistance to Inhibitors of Cholinesterase (RIC-3) has been shown to interfere with assembly and functional maturation of ligand-gated ion channels (LGICs). The RIC3 protein of humans is 369 aas with 2 TMSs. RIC3 promotes functional expression of homomeric alpha-7 and alpha-8 nicotinic acetylcholine receptors at the cell surface. It also promotes functional expression of homomeric serotoninergic 5-HT3 receptors and heteromeric acetylcholine receptors alpha-3/beta-2, alpha-3/beta-4, alpha-4/beta-2 and alpha-4/beta-4 (Halevi et al. 2003). The direct interaction of serotonin type 3A homopentamers (5-HT3A ) with RIC-3 requires the intracellular domain (ICD) of this pLGIC (Nishtala et al. 2016).
References:
Castelán, F., M. Castillo, J. Mulet, S. Sala, F. Sala, E. Domínguez Del Toro, and M. Criado. (2008). Molecular characterization and localization of the RIC-3 protein, an effector of nicotinic acetylcholine receptor expression. J Neurochem 105: 617-627.
Do, H.Q. and M. Jansen. (2023). Binding motif for RIC-3 chaperon protein in serotonin type 3A receptors. J Gen Physiol 155:.
Halevi, S., L. Yassin, M. Eshel, F. Sala, S. Sala, M. Criado, and M. Treinin. (2003). Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression. J. Biol. Chem. 278: 34411-34417.
Loring, R.H. (2022). Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly. Molecules 27:.
Nishtala, S.N., N. Mnatsakanyan, A. Pandhare, C. Leung, and M. Jansen. (2016). Direct interaction of the resistance to inhibitors of cholinesterase type 3 protein with the serotonin receptor type 3A intracellular domain. J Neurochem 137: 528-538.
Examples:
TC#	Name	Organismal Type	Example
8.A.71.1.1	The RIC3 (RIC-3) protein of 369 aas and 2 TMSs. Promotes functional expression of homomeric alpha-7 and alpha-8 nicotinic acetylcholine receptors at the cell surface (Castelán et al. 2008). Also promotes functional expression of homomeric serotoninergic 5-HT3 receptors, and of heteromeric acetylcholine receptors alpha-3/beta-2, alpha-3/beta-4, alpha-4/beta-2 and alpha-4/beta-4.7. It interacts directly with the cytoplasmic domain of the serotonin receptor (TC# 1.A.9.2.3) (Nishtala et al. 2016). The artificial intelligence program AlphaFold2 predicted structures for NACHO and RIC-3. NACHO is highly conserved in sequence and structure across species, but RIC-3 is not. How do disordered RIC-3 isoforms from C. elegans to humans interact with alpha7 nAChR subunits despite having little sequence homology across RIC-3 species? Two models from the literature about how RIC-3 assists alpha7 nAChR assembly have been evaluated, considering recent structural information about the receptor and its chaperones (Loring 2022). The binding motifs for RIC-3 in 5-HT3A receptor subunits at two locations have been identified (Do and Jansen 2023).		RIC3 of Homo sapiens

8.A.71.1.2	Ric-3 protein of 505 aas and 2 TMSs		*Ric-3 of Drosophila melanogaster* (Fruit fly)**

8.A.71.1.3	Ric-3, isoform J of 472 aas and 2 TMSs.		*Ric-3 of Drosophila melanogaster* (Fruit fly)**

8.A.71.1.4	Ric-3 protein of 394 aas and 2 TMSs.		Ric-3 of Caenorhabditis vulgaris