Unraveling the molecular interactions between α7 nicotinic receptor and a RIC3 variant associated with backward speech

Aditi Pradhan, Hayley Mounford, Jessica Peixinho, Edward Rea, Emmanouela Epeslidou, Julia S Scott, Joanna Cull, Susan Maxwell, Richard Webster, David Beeson, Yin Yao Dong, Stefan Prekovic, Isabel Bermudez, Dianne F Newbury*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 α7 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression, and function of human α7 receptors using fluorescent protein tagged α7 nAChR and Förster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and 125I-α-bungarotoxin binding. As expected, the wild-type RIC3 protein was found to increase both cell surface and functional expression of α7 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and α7 protein in the endoplasmic reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and α7, which translates to decreased cell surface and functional expression of α7 nAChR.

Original languageEnglish
Article number129
Pages (from-to)1-13
Number of pages13
JournalCellular and Molecular Life Sciences
Volume81
Issue number1
DOIs
Publication statusPublished - 12 Mar 2024

Keywords

  • Acetylcholinesterase/metabolism
  • Cell Membrane/metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Receptors, Nicotinic/genetics
  • Speech
  • alpha7 Nicotinic Acetylcholine Receptor/metabolism
  • RIC3
  • Nicotinic acetylcholine receptors
  • Backward speech

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