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New Insights Into the Role of Ca(v)2 Protein Family in Calcium Flux Deregulation in Fmr1-KO Neurons
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, nu...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170614/ https://www.ncbi.nlm.nih.gov/pubmed/30319351 http://dx.doi.org/10.3389/fnmol.2018.00342 |
Sumario: | 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 Ca(2+) channels modulating their activity. Collectively these findings suggest that FMRP plays critical roles in Ca(2+) homeostasis during nervous system development. We carried out a functional analysis of Ca(2+) regulation using a calcium imaging approach in Fmr1-KO cultured neurons and we show that these cells display impaired steady state Ca(2+) concentration and an altered entry of Ca(2+) 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 Ca(2+) flux in Fmr1-KO neurons, impacting Ca(2+) 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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