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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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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. |
format | Online Article Text |
id | pubmed-9700043 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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