Quantitative cortical synapse proteomics of a transgenic migraine mouse model with mutated CaV2.1 calcium channels |
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Authors: | Oleg I. Klychnikov Ka Wan Li Igor A. Sidorov Maarten Loos Sabine Spijker Ludo A. M. Broos Rune R. Frants Michel D. Ferrari Oleg A. Mayboroda André M. Deelder August B. Smit Arn M. J. M. van den Maagdenberg |
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Affiliation: | 1. Biomolecular Mass Spectrometry Unit, Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands;2. These authors have contributed equally to this work.;3. Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands;4. Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands;5. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;6. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands |
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Abstract: | Familial hemiplegic migraine type 1 (FHM1) is caused by missense mutations in the CACNA1A gene that encodes the α1A pore‐forming subunit of CaV2.1 Ca2+ channels. Knock‐in (KI) transgenic mice expressing CaV2.1 Ca2+ channels with a human pathogenic FHM1 mutation reveal enhanced glutamatergic neurotransmission in the cortex. In this study, we employed an iTRAQ‐based LC‐LC MS/MS approach to identify differentially expressed proteins in cortical synapse proteomes of Cacna1a R192Q KI and wild‐type mice. All expression differences determined were subtle and in the range of 10–30%. Observed upregulated proteins in the mutant mice are involved in processes, such as neurite outgrowth and actin dynamics, vesicle turnover, and glutamate transporters. Our data support the view that in Cacna1a R192Q KI mice, several compensatory mechanisms counterbalancing a dysregulated glutamatergic signaling have come into effect. We propose that such adaptation mechanisms at the synapse level may play a role in the pathophysiology of FHM and possibly in the common forms of migraine. |
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Keywords: | Animal proteomics Familial hemiplegic migraine iTRAQ Knock‐in mice Quantitative proteomics Synapse |
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