Lin Da-Ting, Makino Yuichi, Sharma Kamal, Hayashi Takashi, Neve Rachael, Takamiya Kogo, Huganir Richard L
Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nat Neurosci. 2009 Jul;12(7):879-87. doi: 10.1038/nn.2351. Epub 2009 Jun 7.
The insertion of AMPA receptors (AMPARs) into the plasma membrane is an important step in the synaptic delivery of AMPARs during the expression of synaptic plasticity. However, the molecular mechanisms regulating AMPAR insertion remain elusive. By directly visualizing individual insertion events of the AMPAR subunit GluR1 in rodents, we found that the protein 4.1N was required for activity-dependent GluR1 insertion. Protein kinase C (PKC) phosphorylation of the serine 816 (S816) and S818 residues of GluR1 enhanced 4.1N binding to GluR1 and facilitated GluR1 insertion. In addition, palmitoylation of GluR1 C811 residue modulated PKC phosphorylation and GluR1 insertion. Finally, disrupting 4.1N-dependent GluR1 insertion decreased surface expression of GluR1 and the expression of long-term potentiation. Our study uncovers a previously unknown mechanism that governs activity-dependent GluR1 trafficking, reveals an interaction between AMPAR palmitoylation and phosphorylation, and underscores the functional importance of 4.1N in AMPAR trafficking and synaptic plasticity.
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARs）插入质膜是突触可塑性表达过程中AMPARs突触传递的重要一步。然而，调节AMPAR插入的分子机制仍不清楚。通过直接观察啮齿动物中AMPAR亚基GluR1的单个插入事件，我们发现蛋白4.1N是活性依赖的GluR1插入所必需的。蛋白激酶C（PKC）对GluR1的丝氨酸816（S816）和S818残基的磷酸化增强了4.1N与GluR1的结合，并促进了GluR1的插入。此外，GluR1 C811残基的棕榈酰化调节PKC磷酸化和GluR1插入。最后，破坏4.1N依赖的GluR1插入会降低GluR1的表面表达和长时程增强的表达。我们的研究揭示了一种以前未知的控制活性依赖的GluR1转运的机制，揭示了AMPAR棕榈酰化和磷酸化之间的相互作用，并强调了4.1N在AMPAR转运和突触可塑性中的功能重要性。
