Pradhan_2024_Cell.Mol.Life.Sci_81_129

Recent work putatively linked a rare genetic variant of the chaperone Resistant to Inhibitors of acetylcholinesterase (RIC3) (NM_024557.4:c.262G > A, NP_078833.3:p.G88R) to a unique ability to speak backwards, a language skill that is associated with exceptional working memory capacity. RIC3 is important for the folding, maturation, and functional expression of alpha7 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression, and function of human alpha7 receptors using fluorescent protein tagged alpha7 nAChR and Forster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and (125)I-alpha-bungarotoxin binding. As expected, the wild-type RIC3 protein was found to increase both cell surface and functional expression of alpha7 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and alpha7 protein in the endoplasmic reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and alpha7, which translates to decreased cell surface and functional expression of alpha7 nAChR.