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Both Orai1 and TRPC1 are Involved in Excessive Store-Operated Calcium Entry in Striatal Neurons Expressing Mutant Huntingtin Exon 1

It has been previously reported that N-terminus of mutant huntingtin (product of the 1st exon) is sufficient to cause a Huntington's disease (HD) pathological phenotype. In view of recent data suggesting that improper regulation of store-operated calcium (SOC) channels is involved in neurodegen...

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Autores principales: Vigont, Vladimir, Kolobkova, Yulia, Skopin, Anton, Zimina, Olga, Zenin, Valery, Glushankova, Lyuba, Kaznacheyeva, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4656824/
https://www.ncbi.nlm.nih.gov/pubmed/26635623
http://dx.doi.org/10.3389/fphys.2015.00337
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author Vigont, Vladimir
Kolobkova, Yulia
Skopin, Anton
Zimina, Olga
Zenin, Valery
Glushankova, Lyuba
Kaznacheyeva, Elena
author_facet Vigont, Vladimir
Kolobkova, Yulia
Skopin, Anton
Zimina, Olga
Zenin, Valery
Glushankova, Lyuba
Kaznacheyeva, Elena
author_sort Vigont, Vladimir
collection PubMed
description It has been previously reported that N-terminus of mutant huntingtin (product of the 1st exon) is sufficient to cause a Huntington's disease (HD) pathological phenotype. In view of recent data suggesting that improper regulation of store-operated calcium (SOC) channels is involved in neurodegenerative processes, we investigated influence of expression of the mutant huntingtin N-terminal fragment (Htt138Q-1exon) on SOC entry (SOCE) in mouse neuroblastoma cells (Neuro-2a) and in primary culture of medium spiny neurons (MSNs) isolated from mice. The results show that SOCE in these cells is enhanced upon lentiviral expression of the Htt138Q-1exon. Moreover, we demonstrated that RNAi-mediated knockdown of TRPC1, Orai1, or STIM1 proteins leads to dramatic reduction of abnormal SOCE in both Neuro-2a and MSNs, expressing Htt138Q-1exon. Thus, we concluded that abnormal SOCE in these cells is maintained by both TRPC1- and Orai1-containing channels and required STIM1 for its activation. Furthermore, EVP4593 compound previously tested as a potential anti-HD drug in a Drosophila screening system has proved to be capable of reducing SOCE to the normal level in MSNs expressing the Htt138Q-1exon.
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spelling pubmed-46568242015-12-03 Both Orai1 and TRPC1 are Involved in Excessive Store-Operated Calcium Entry in Striatal Neurons Expressing Mutant Huntingtin Exon 1 Vigont, Vladimir Kolobkova, Yulia Skopin, Anton Zimina, Olga Zenin, Valery Glushankova, Lyuba Kaznacheyeva, Elena Front Physiol Physiology It has been previously reported that N-terminus of mutant huntingtin (product of the 1st exon) is sufficient to cause a Huntington's disease (HD) pathological phenotype. In view of recent data suggesting that improper regulation of store-operated calcium (SOC) channels is involved in neurodegenerative processes, we investigated influence of expression of the mutant huntingtin N-terminal fragment (Htt138Q-1exon) on SOC entry (SOCE) in mouse neuroblastoma cells (Neuro-2a) and in primary culture of medium spiny neurons (MSNs) isolated from mice. The results show that SOCE in these cells is enhanced upon lentiviral expression of the Htt138Q-1exon. Moreover, we demonstrated that RNAi-mediated knockdown of TRPC1, Orai1, or STIM1 proteins leads to dramatic reduction of abnormal SOCE in both Neuro-2a and MSNs, expressing Htt138Q-1exon. Thus, we concluded that abnormal SOCE in these cells is maintained by both TRPC1- and Orai1-containing channels and required STIM1 for its activation. Furthermore, EVP4593 compound previously tested as a potential anti-HD drug in a Drosophila screening system has proved to be capable of reducing SOCE to the normal level in MSNs expressing the Htt138Q-1exon. Frontiers Media S.A. 2015-11-24 /pmc/articles/PMC4656824/ /pubmed/26635623 http://dx.doi.org/10.3389/fphys.2015.00337 Text en Copyright © 2015 Vigont, Kolobkova, Skopin, Zimina, Zenin, Glushankova and Kaznacheyeva. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Vigont, Vladimir
Kolobkova, Yulia
Skopin, Anton
Zimina, Olga
Zenin, Valery
Glushankova, Lyuba
Kaznacheyeva, Elena
Both Orai1 and TRPC1 are Involved in Excessive Store-Operated Calcium Entry in Striatal Neurons Expressing Mutant Huntingtin Exon 1
title Both Orai1 and TRPC1 are Involved in Excessive Store-Operated Calcium Entry in Striatal Neurons Expressing Mutant Huntingtin Exon 1
title_full Both Orai1 and TRPC1 are Involved in Excessive Store-Operated Calcium Entry in Striatal Neurons Expressing Mutant Huntingtin Exon 1
title_fullStr Both Orai1 and TRPC1 are Involved in Excessive Store-Operated Calcium Entry in Striatal Neurons Expressing Mutant Huntingtin Exon 1
title_full_unstemmed Both Orai1 and TRPC1 are Involved in Excessive Store-Operated Calcium Entry in Striatal Neurons Expressing Mutant Huntingtin Exon 1
title_short Both Orai1 and TRPC1 are Involved in Excessive Store-Operated Calcium Entry in Striatal Neurons Expressing Mutant Huntingtin Exon 1
title_sort both orai1 and trpc1 are involved in excessive store-operated calcium entry in striatal neurons expressing mutant huntingtin exon 1
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4656824/
https://www.ncbi.nlm.nih.gov/pubmed/26635623
http://dx.doi.org/10.3389/fphys.2015.00337
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