Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky Ca(2+) channels and activation of store-operated Ca(2+) entry

Mutations in all subtypes of the inositol 1,4,5-trisphosphate receptor Ca(2+) release channel are associated with human diseases. In this report, we investigated the functionality of three neuropathy-associated missense mutations in IP(3)R3 (V615M, T1424M, and R2524C). The mutants only exhibited fun...

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Autores principales: Terry, Lara E., Arige, Vikas, Neumann, Julika, Wahl, Amanda M., Knebel, Taylor R., Chaffer, James W., Malik, Sundeep, Liston, Adrian, Humblet-Baron, Stephanie, Bultynck, Geert, Yule, David I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700043/
https://www.ncbi.nlm.nih.gov/pubmed/36444295
http://dx.doi.org/10.1016/j.isci.2022.105523
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author Terry, Lara E.
Arige, Vikas
Neumann, Julika
Wahl, Amanda M.
Knebel, Taylor R.
Chaffer, James W.
Malik, Sundeep
Liston, Adrian
Humblet-Baron, Stephanie
Bultynck, Geert
Yule, David I.
author_facet Terry, Lara E.
Arige, Vikas
Neumann, Julika
Wahl, Amanda M.
Knebel, Taylor R.
Chaffer, James W.
Malik, Sundeep
Liston, Adrian
Humblet-Baron, Stephanie
Bultynck, Geert
Yule, David I.
author_sort Terry, Lara E.
collection PubMed
description Mutations in all subtypes of the inositol 1,4,5-trisphosphate receptor Ca(2+) release channel are associated with human diseases. In this report, we investigated the functionality of three neuropathy-associated missense mutations in IP(3)R3 (V615M, T1424M, and R2524C). The mutants only exhibited function when highly over-expressed compared to endogenous hIP(3)R3. All variants resulted in elevated basal cytosolic Ca(2+) levels, decreased endoplasmic reticulum Ca(2+) store content, and constitutive store-operated Ca(2+) entry in the absence of any stimuli, consistent with a leaky IP(3)R channel pore. These variants differed in channel function; when stably over-expressed the R2524C mutant was essentially dead, V615M was poorly functional, and T1424M exhibited activity greater than that of the corresponding wild-type following threshold stimulation. These results demonstrate that a common feature of these mutations is decreased IP(3)R3 function. In addition, these mutations exhibit a novel phenotype manifested as a constitutively open channel, which inappropriately gates SOCE in the absence of stimulation.
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spelling pubmed-97000432022-11-27 Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky Ca(2+) channels and activation of store-operated Ca(2+) entry Terry, Lara E. Arige, Vikas Neumann, Julika Wahl, Amanda M. Knebel, Taylor R. Chaffer, James W. Malik, Sundeep Liston, Adrian Humblet-Baron, Stephanie Bultynck, Geert Yule, David I. iScience Article Mutations in all subtypes of the inositol 1,4,5-trisphosphate receptor Ca(2+) release channel are associated with human diseases. In this report, we investigated the functionality of three neuropathy-associated missense mutations in IP(3)R3 (V615M, T1424M, and R2524C). The mutants only exhibited function when highly over-expressed compared to endogenous hIP(3)R3. All variants resulted in elevated basal cytosolic Ca(2+) levels, decreased endoplasmic reticulum Ca(2+) store content, and constitutive store-operated Ca(2+) entry in the absence of any stimuli, consistent with a leaky IP(3)R channel pore. These variants differed in channel function; when stably over-expressed the R2524C mutant was essentially dead, V615M was poorly functional, and T1424M exhibited activity greater than that of the corresponding wild-type following threshold stimulation. These results demonstrate that a common feature of these mutations is decreased IP(3)R3 function. In addition, these mutations exhibit a novel phenotype manifested as a constitutively open channel, which inappropriately gates SOCE in the absence of stimulation. Elsevier 2022-11-07 /pmc/articles/PMC9700043/ /pubmed/36444295 http://dx.doi.org/10.1016/j.isci.2022.105523 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Terry, Lara E.
Arige, Vikas
Neumann, Julika
Wahl, Amanda M.
Knebel, Taylor R.
Chaffer, James W.
Malik, Sundeep
Liston, Adrian
Humblet-Baron, Stephanie
Bultynck, Geert
Yule, David I.
Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky Ca(2+) channels and activation of store-operated Ca(2+) entry
title Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky Ca(2+) channels and activation of store-operated Ca(2+) entry
title_full Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky Ca(2+) channels and activation of store-operated Ca(2+) entry
title_fullStr Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky Ca(2+) channels and activation of store-operated Ca(2+) entry
title_full_unstemmed Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky Ca(2+) channels and activation of store-operated Ca(2+) entry
title_short Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky Ca(2+) channels and activation of store-operated Ca(2+) entry
title_sort missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky ca(2+) channels and activation of store-operated ca(2+) entry
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700043/
https://www.ncbi.nlm.nih.gov/pubmed/36444295
http://dx.doi.org/10.1016/j.isci.2022.105523
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