TY - JOUR
T1 - Unraveling the molecular interactions between α7 nicotinic receptor and a RIC3 variant associated with backward speech
AU - Pradhan, Aditi
AU - Mounford, Hayley
AU - Peixinho, Jessica
AU - Rea, Edward
AU - Epeslidou, Emmanouela
AU - Scott, Julia S
AU - Cull, Joanna
AU - Maxwell, Susan
AU - Webster, Richard
AU - Beeson, David
AU - Dong, Yin Yao
AU - Prekovic, Stefan
AU - Bermudez, Isabel
AU - Newbury, Dianne F
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/3/12
Y1 - 2024/3/12
N2 - 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.
AB - 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.
KW - Acetylcholinesterase/metabolism
KW - Cell Membrane/metabolism
KW - Humans
KW - Intracellular Signaling Peptides and Proteins/metabolism
KW - Receptors, Nicotinic/genetics
KW - Speech
KW - alpha7 Nicotinic Acetylcholine Receptor/metabolism
KW - RIC3
KW - Nicotinic acetylcholine receptors
KW - Backward speech
UR - http://www.scopus.com/inward/record.url?scp=85187498018&partnerID=8YFLogxK
U2 - 10.1007/s00018-024-05149-8
DO - 10.1007/s00018-024-05149-8
M3 - Article
C2 - 38472514
SN - 1420-682X
VL - 81
SP - 1
EP - 13
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 1
M1 - 129
ER -