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Fragile X Mental Retardation Protein Regulates Protein Expression and mRNA Translation of the Potassium Channel Kv4.2
Open accessAbstract
A prominent characteristic of the inherited intellectual impairment disease fragile X syndrome (FXS) is neuronal hyperexcitability, resulting in a variety of symptoms, such as hyperactivity, increased sensitivity to sensory stimuli, and a high incidence of epileptic seizures. These symptoms account for a significant part of the disease pattern, but the underlying molecular mechanisms of neuronal hyperexcitability in FXS remain poorly understood. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), which regulates synaptic protein synthesis and is a key player to limit signaling pathways downstream of metabotropic glutamate receptors 1/5 (mGlu1/5). Recent findings suggest that FMRP might also directly regulate voltage-gated potassium channels. Here, we show that total and plasma membrane protein levels of Kv4.2, the major potassium channel regulating hippocampal neuronal excitability, are reduced in the brain of an FXS mouse model. Antagonizing mGlu5 activity with 2-methyl-6-(phenylethynyl)-pyridine (MPEP) partially rescues reduced surface Kv4.2 levels in Fmr1 knock-out (KO) mice, suggesting that excess mGlu1/5 signal activity contributes to Kv4.2 dysregulation. As an additional mechanism, we show that FMRP is a positive regulator of Kv4.2 mRNA translation and protein expression and associates with Kv4.2 mRNA in vivo and in vitro . Our results suggest that absence of FMRP-mediated positive control of Kv4.2 mRNA translation, protein expression, and plasma membrane levels might contribute to excess neuronal excitability in Fmr1 KO mice, and thus imply a potential mechanism underlying FXS-associated epilepsy.
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“Indeed, FMRP is not only involved in translational repression, it is also a translational enhancer (Bechara et al., 2009; Gross et al., 2011; Kwan et al., 2012; Tabet et al., 2016)”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Gross et al., 2011
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Cites
Reinsertion or Degradation of AMPA Receptors Determined by Activity-Dependent Endocytic Sorting
Ehlers, M. D. (2000) · Neuron · doi:10.1016/s0896-6273(00)00129-x · Cited by 1,096
Fragile X Syndrome: Loss of Local mRNA Regulation Alters Synaptic Development and Function
Bassell, G. J., & Warren, S. T. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.004 · Cited by 1,051
Self-citationCorrection of Fragile X Syndrome in Mice
Dölen, G., Osterweil, E., Rao, B. S. S., Smith, G. B., Auerbach, B. D., Chattarji, S., & Bear, M. F. (2007) · Neuron · doi:10.1016/j.neuron.2007.12.001 · Cited by 979
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Advances in the Treatment of Fragile X Syndrome
Hagerman, R. J., Berry-Kravis, E., Kaufmann, W. E., Ono, M. Y., Tartaglia, N., Lachiewicz, A., Kronk, R., Delahunty, C., Hessl, D., Visootsak, J., et al. (2009) · Pediatrics · doi:10.1542/peds.2008-0317 · Cited by 596
Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP
Yan, Q. J., Rammal, M., Tranfaglia, M., & Bauchwitz, R. P. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2005.06.004 · Cited by 521
Muddashetty, R. S., Kelić, S., Gross, C., Xu, M., & Bassell, G. J. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.0937-07.2007 · Cited by 421
Self-citationAntar, L. N., Afroz, R., Dictenberg, J. B., Carroll, R. C., & Bassell, G. J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.0099-04.2004 · Cited by 411
Self-citationStructure and Function of Kv4-Family Transient Potassium Channels
Birnbaum, S. G., Varga, A. W., Yuan, L., Anderson, A. E., Sweatt, J. D., & Schrader, L. A. (2004) · Physiological Reviews · doi:10.1152/physrev.00039.2003 · Cited by 369
Chen, X., Yuan, L., Zhao, C., Birnbaum, S. G., Frick, A., Jung, W. E., Schwarz, T. L., Sweatt, J. D., & Johnston, D. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2667-06.2006 · Cited by 306
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Sorted by citations
Altered Neuronal and Circuit Excitability in Fragile X Syndrome
Contractor, A., Klyachko, V. A., & Portera‐Cailliau, C. (2015) · Neuron · doi:10.1016/j.neuron.2015.06.017 · Cited by 418
Deng, P.-Y., Rotman, Z., Blundon, J. A., Cho, Y., Cui, J., Cavalli, V., Zakharenko, S. S., & Klyachko, V. A. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.018 · Cited by 354
Lisman, J., Cooper, K., Sehgal, M., & Silva, A. J. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0076-6 · Cited by 351
Masini, E., Loi, E., Vega-Benedetti, A. F., Carta, M., Doneddu, G., Fadda, R., & Zavattari, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218290 · Cited by 310
Dysregulation and restoration of translational homeostasis in fragile X syndrome
Richter, J. D., Bassell, G. J., & Klann, E. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn4001 · Cited by 275
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Metadata
- Authors
- Gross, C., Yao, X., Pong, D. L., Jeromin, A., & Bassell, G. J.
- Affiliations
- Emory University (US)
- Banyan Biomarkers (United States) (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-04-13
- Volume
- 31
- Issue
- 15
- Pages
- 5693-5698
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3089949
- OpenAlex
- W1992696632
- Cited by
- 161
- References
- 26
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 10 · 2021: 8 · 2020: 11 · 2019: 18 · 2018: 14 · 2017: 8 · 2016: 10 · 2015: 18 · 2014: 8 · 2013: 14 · 2012: 9
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH085617, MH085617)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD024064)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- fragile X syndrome, FMRP, Kv4.2, voltage-gated potassium channels, neuronal hyperexcitability, MPEP, mRNA translation regulation, protein expression regulation, Fmr1 knockout mice, hippocampal excitability
- MeSH terms
- Actins, Animals, Dendrites, Fluorescent Antibody Technique, Mice, Inbred C57BL, Phenotype, Polyribosomes, RNA, Messenger, Seizures, Synapses, Protein Biosynthesis, Blotting, Western, DNA Primers, Receptors, Metabotropic Glutamate, Mice, Knockout, Biotinylation, 5' Untranslated Regions, 3' Untranslated Regions, Immunoprecipitation, Mice, Shal Potassium Channels, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein, Receptor, Metabotropic Glutamate 5
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