Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors.
Activity-dependent targeting of NMDA receptors (NMDARs) is a key feature of synapse formation and plasticity. Although mechanisms for rapid trafficking of glutamate receptors have been identified, the molecular events underlying chronic accumulation or loss of synaptic NMDARs have remained unclear. Here we demonstrate that activity controls NMDAR synaptic accumulation by regulating forward trafficking at the endoplasmic reticulum (ER). ER export is accelerated by the alternatively spliced C2' domain of the NR1 subunit and slowed by the C2 splice cassette. This mRNA splicing event at the C2/C2' site is activity dependent, with C2' variants predominating upon activity blockade and C2 variants abundant with increased activity. The switch to C2' accelerates NMDAR forward trafficking by enhancing recruitment of nascent NMDARs to ER exit sites via binding of a divaline motif within C2' to COPII coats. These results define a novel pathway underlying activity-dependent targeting of glutamate receptors, providing an unexpected mechanistic link between activity, mRNA splicing, and membrane trafficking during excitatory synapse modification.
Mu
Yuanyue
Y
Department of Neurobiology, Duke University Medical Center, Box 3209, Durham, NC 27710, USA.
Otsuka
Takeshi
T
Horton
April C
AC
Scott
Derek B
DB
Ehlers
Michael D
MD
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D022181:COP-Coated Vesicles / Q000378:metabolism; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002522:Chlorocebus aethiops; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005091:Exons; D018756:GABA Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015151:Immunoblotting; D008164:Luminescent Proteins; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D000779:Anesthetics, Local; D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D008164:Luminescent Proteins; C409466:NR1 NMDA receptor; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C120531:Shank1 protein, rat; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine; D001640:Bicuculline