Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density.
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 (Ca(V)) channels. Here we show that the functional expression of neuronal N-type Ca(V) channels (Ca(V)2.2) is regulated by fragile X mental retardation protein (FMRP). We find that FMRP knockdown in dorsal root ganglion neurons increases Ca(V) channel density in somata and in presynaptic terminals. We then show that FMRP controls Ca(V)2.2 surface expression by targeting the channels to the proteasome for degradation. The interaction between FMRP and Ca(V)2.2 occurs between the carboxy-terminal domain of FMRP and domains of Ca(V)2.2 known to interact with the neurotransmitter release machinery. Finally, we show that FMRP controls synaptic exocytosis via Ca(V)2.2 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.
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Laurent
L
Ferron
1] Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK [2].
Manuela
M
Nieto-Rostro
1] Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK [2].
John S
JS
Cassidy
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Annette C
AC
Dolphin
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D002460:Cell Line; D005089:Exocytosis / Q000502:physiology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism*
D002118:Calcium; D020864:Calcium Channels, N-Type; D051860:Fragile X Messenger Ribonucleoprotein 1