Neuron 67, 239C252. NMDARs. Loss of SNX27 or CaMKII function blocks the glycine-induced increase in GluN2A-NMDARs around the neuronal membrane. Interestingly, mutations of Ser-1459, including the rare S1459G human epilepsy variant, prolong the decay occasions of NMDAR-mediated synaptic currents in heterosynapses by increasing the duration of channel opening. These findings not only identify a critical role of Ser-1459 phosphorylation in regulating the function of NMDARs, but they also explain how the S1459G variant dysregulates NMDAR function. Graphical Abstract In brief Yong et al. identify that activity-dependent phosphorylation of Ser-1459 in the GluN2A C-terminal domain name by CaMKII promotes its conversation with the SNX27-retromer complex, thereby enhancing the surface expression of NMDARs during synaptic potentiation. Mutations of Ser-1459 prolong the decay occasions of NMDAR-mediated synaptic currents by increasing the duration of channel opening. INTRODUCTION NMDA receptors (NMDARs) are ionotropic glutamate receptors that act as coincidence detectors of presynaptic glutamate release and postsynaptic membrane depolarization. NMDAR-mediated excitatory postsynaptic currents (EPSCs) mediate the flux of calcium (Ca2+) into the postsynaptic compartment, triggering downstream Ca2+-dependent signaling cascades that are crucial for neuronal development, synaptic and structural plasticity, learning, and memory (Bosch and Hayashi, 2012; Morris, 2013; Nicoll and Roche, 2013; Paoletti et al., 2013). Pharmacological and genetic manipulations that disrupt the expression and function of NMDARs often cause impairments in synaptic plasticity and cognitive deficits in animal models. Importantly, NMDAR dysfunction has also been implicated in many human neurological disorders, including stroke, epilepsy, Alzheimers disease, neuropathic pain, and schizophrenia (Zhou and Sheng, 2013). Moreover, genes that encode NMDAR subunits are remarkably intolerant to mutations, which have been associated with various human neurodevelopmental and neuropsychiatric disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia (Myers et al., 2019; XiangWei et al., 2018). Most NMDARs in the forebrain are heterotetramers composed of two obligatory GluN1 subunits and two identical (diheteromeric) Rabbit polyclonal to ALS2 or different (triheteromeric) GluN2 subunits (Paoletti et al., 2013; Sanz-Clemente et al., 2013; Stroebel et al., 2018; Vieira et al., 2020). Among the four different glutamate-binding GluN2 subunits, GluN2A and GluN2B, each of which confers NMDARs with distinct ion channel properties and intracellular trafficking pathways (Sanz-Clemente et al., 2013; Vieira et al., 2020; Wyllie et al., 2013), are highly expressed in the hippocampus and cortex (Gray et al., 2011). The expression of synaptic NMDARs is usually regulated during development as they undergo a switch in their subunit composition from GluN2B- to GluN2A-containing receptors (Monyer et al., 1994; Sheng et al., 1994). In the developing visual cortex, the switch in NMDAR subunit composition during the crucial period can be rapidly driven by sensory experience (Quinlan et al., 1999). The same phenomenon has also been observed following the induction of long-term potentiation (LTP) in acute hippocampal slices from young mice (Bellone and Nicoll, 2007), organotypic hippocampal slices (Barria and Malinow, 2002; Grosshans et al., 2002), and primary neuronal cultures (Swanger et al., 2013; Zhang et al., 2015). Given that GluN2A-containing NMDARs have a higher channel open probability and a faster deactivation time than do those made up of the GluN2B subunit, such an activity-dependent switch in NMDAR subunit composition at synapses will have major implications for dendritic integration, circuit refinement, and synaptic plasticity (Barria and Malinow, 2005; Kirkwood et al., 1996; Shipton and Paulsen, 2013; Yashiro and Philpot, 2008). Despite this, the molecular mechanisms underlying the activity-dependent trafficking of GluN2A-containing NMDARs during synaptic plasticity remain poorly understood. The precise subcellular localization, membrane trafficking, and synaptic targeting of GluN2-made up of NMDARs are largely determined by protein-protein interactions and post-translational modifications in the cytoplasmic C-terminal tails (Lussier et al., 2015; Vieira et al., 2020). Sorting nexin 27 (SNX27) is usually a highly conserved regulator of cargo retrieval from endosomes to the plasma membrane that directly interacts with various GluN2 subunits of NMDARs through its N-terminal PDZ (postsynaptic density 95/disc-large/zona occluden-1) domain name (Cai et al., 2011; Clairfeuille et al., 2016; Mota Vieira et al., 2020). SNX27 forms a complex with retromer (a heterotrimer of VPS26, VPS29, and VSP35) via its direct conversation with VPS26, and it acts as a cargo adaptor for retromer-mediated transport from intracellular endosomes to the cell surface (Cullen and Korswagen, 2011; Gallon et al., 2014). Genetic deletion of SNX27 causes TC-H 106 a profound loss of total and surface NMDAR expression due to a defect in the endosomal trafficking pathway, underscoring its crucial role in regulating NMDAR recycling in the brain (Wang et TC-H 106 TC-H 106 al., 2013). The high-affinity binding of the SNX27 PDZ domain name to its cargo molecules generally involves the formation of an electrostatic clamp, which is usually formed constitutively by acidic residues at the (?3) and (?5) positions upstream of the PDZ binding motif, or, alternatively, by phosphorylation of serine or threonine residues in these positions (Clairfeuille et al., 2016). The.
