Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

Laurent Ferron (), Manuela Nieto-Rostro, John S. Cassidy and Annette C. Dolphin ()
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Laurent Ferron: Physiology and Pharmacology, University College London
Manuela Nieto-Rostro: Physiology and Pharmacology, University College London
John S. Cassidy: Physiology and Pharmacology, University College London
Annette C. Dolphin: Physiology and Pharmacology, University College London

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: Abstract Fragile X syndrome (FXS), the most common heritable form of mental retardation, is characterized by synaptic dysfunction. Synaptic transmission depends critically on presynaptic calcium entry via voltage-gated calcium (CaV) channels. Here we show that the functional expression of neuronal N-type CaV channels (CaV2.2) is regulated by fragile X mental retardation protein (FMRP). We find that FMRP knockdown in dorsal root ganglion neurons increases CaV channel density in somata and in presynaptic terminals. We then show that FMRP controls CaV2.2 surface expression by targeting the channels to the proteasome for degradation. The interaction between FMRP and CaV2.2 occurs between the carboxy-terminal domain of FMRP and domains of CaV2.2 known to interact with the neurotransmitter release machinery. Finally, we show that FMRP controls synaptic exocytosis via CaV2.2 channels. Our data indicate that FMRP is a potent regulator of presynaptic activity, and its loss is likely to contribute to synaptic dysfunction in FXS.

Date: 2014
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DOI: 10.1038/ncomms4628

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