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Beschreibung

Synaptic functional regulator FMR1 (UniProt: P35922, also known as Fragile X mental retardation protein 1 homolog, FMRP, Protein FMR-1, mFmr1p) is encoded by the Fmr1 (also known as Fmr-1) gene (Gene ID: 14265) in murine species. FMR-1 is a homodimeric multifunctional polyribosome-associated RNA-binding protein predominantly found in the brain. It can also form heterodimer with FXR1 in a methylation-dependent manner. It shuttles between nucleus and cytoplasm in a XPO1/CRM1-dependent manner and plays a central role in neuronal development and synaptic plasticity through the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of a subset of mRNAs. FMR-1 plays a role in mRNA nuclear export and together with export factor NXF2, it is involved in the regulation of the NXF1 mRNA stability in neurons. It stabilizes the scaffolding postsynaptic density protein DLG4/PSD-95 and the myelin basic protein mRNAs in hippocampal neurons and glial cells, respectively and this stabilization is further increased in response to metabotropic glutamate receptor (mGluR) stimulation. In response to mGluR stimulation, FMR1-target mRNAs are rapidly derepressed, allowing for local translation at synapses. FMR-1 is shown to play a role in the modulation of the sodium-activated potassium channel KCNT1 gating activity and negatively regulate the voltage-dependent calcium channel current density in soma and presynaptic terminals of dorsal root ganglion (DRG) neurons. FMR-1 is phosphorylated on several serine residues and phosphorylation at serine 499 is required for phosphorylation of other nearby serine residues. Although phosphorylation has no effect on the binding of individual mRNA species, it may affect the association with polyribosome.