期刊
FRONTIERS IN MOLECULAR NEUROSCIENCE
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fnmol.2018.00342
关键词
Fragile X syndrome; Ca(v)2.1; calcium homeostasis; ratiometric calcium imaging; Cacna1a
资金
- Universite Cote d'Azur (UCA)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Centre National de la Recherche Scientifique (CNRS)
- Agence Nationale de la Recherche [ANR-12-BSV4-0020, ANR-12-SVSE8-0022]
- Fondation pour la Recherche Medicale (FRM) [DEQ20140329490]
- Investments for the Future, through the LABEX SIGNALIFE program [ANR-11-LABX-0028-013]
- Fondation Jerome Lejeune
- FRAXA Foundation
- LABEX SIGNALIFE program
- [ANR-15-CE16-0015]
- [FRM-ING20140129004]
- Agence Nationale de la Recherche (ANR) [ANR-12-BSV4-0020] Funding Source: Agence Nationale de la Recherche (ANR)
Fragile X syndrome (FXS), the most common form of inherited intellectual disability (ID) and a leading cause of autism, results from the loss of expression of the Fmr1 gene which encodes the RNA-binding protein Fragile X Mental Retardation Protein (FMRP). Among the thousands mRNA targets of FMRP, numerous encode regulators of ion homeostasis. It has also been described that FMRP directly interacts with Ca2+ channels modulating their activity. Collectively these findings suggest that FMRP plays critical roles in Ca2+ homeostasis during nervous system development. We carried out a functional analysis of Ca2+ regulation using a calcium imaging approach in Fmr1-KO cultured neurons and we show that these cells display impaired steady state Ca2+ concentration and an altered entry of Ca2+ after KCl-triggered depolarization. Consistent with these data, we show that the protein product of the Cacna1a gene, the pore-forming subunit of the Ca(v)2.1 channel, is less expressed at the plasma membrane of Fmr1-KO neurons compared to wild-type (WT). Thus, our findings point out the critical role that Ca(v)2.1 plays in the altered Ca2+ flux in Fmr1-KO neurons, impacting Ca2+ homeostasis of these cells. Remarkably, we highlight a new phenotype of cultured Fmr1-KO neurons that can be considered a novel cellular biomarker and is amenable to small molecule screening and identification of new drugs to treat FXS.
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