8 research outputs found
Tyrosine Phosphorylation Regulates the Endocytosis and Surface Expression of GluN3A-Containing NMDA Receptors
Selective control of receptor trafficking provides a mechanism for remodeling
the receptor composition of excitatory synapses, and thus supports synaptic
transmission, plasticity, and development. GluN3A (formerly NR3A) is a
nonconventional member of the NMDA receptor (NMDAR) subunit family, which
endows NMDAR channels with low calcium permeability and reduced magnesium
sensitivity compared with NMDARs comprising only GluN1 and GluN2 subunits.
Because of these special properties, GluN3A subunits act as a molecular brake
to limit the plasticity and maturation of excitatory synapses, pointing toward
GluN3A removal as a critical step in the development of neuronal circuitry.
However, the molecular signals mediating GluN3A endocytic removal remain
unclear. Here we define a novel endocytic motif (YWL), which is located within
the cytoplasmic C-terminal tail of GluN3A and mediates its binding to the
clathrin adaptor AP2. Alanine mutations within the GluN3A endocytic motif
inhibited clathrin-dependent internalization and led to accumulation of
GluN3A-containing NMDARs at the cell surface, whereas mimicking
phosphorylation of the tyrosine residue promoted internalization and reduced
cell-surface expression as shown by immunocytochemical and
electrophysiological approaches in recombinant systems and rat neurons in
primary culture. We further demonstrate that the tyrosine residue is
phosphorylated by Src family kinases, and that Src-activation limits surface
GluN3A expression in neurons. Together, our results identify a new molecular
signal for GluN3A internalization that couples the functional surface
expression of GluN3A-containing receptors to the phosphorylation state of
GluN3A subunits, and provides a molecular framework for the regulation of
NMDAR subunit composition with implications for synaptic plasticity and
neurodevelopment
Expression of Cocaine-Evoked Synaptic Plasticity by GluN3A-Containing NMDA Receptors
Drug-evoked synaptic plasticity in the mesolimbic dopamine (DA) system reorganizes neural circuits that may lead to addictive behavior. The first cocaine exposure potentiates AMPAR excitatory postsynaptic currents (EPSCs) onto DA neurons of the VTA but reduces the amplitude of NMDAR-EPSCs. While plasticity of AMPAR transmission is expressed by insertion of calcium (Ca(2+))-permeable GluA2-lacking receptors, little is known about the expression mechanism for altered NMDAR transmission. Combining ex vivo patch-clamp recordings, mouse genetics, and subcellular Ca(2+) imaging, we observe that cocaine drives the insertion of NMDARs that are quasi-Ca(2+)-impermeable and contain GluN3A and GluN2B subunits. These GluN3A-containing NMDARs appear necessary for the expression of cocaine-evoked plasticity of AMPARs. We identify an mGluR1-dependent mechanism to remove these noncanonical NMDARs that requires Homer/Shank interaction and protein synthesis. Our data provide insight into the early cocaine-driven reorganization of glutamatergic transmission onto DA neurons and offer GluN3A-containing NMDARs as new targets in drug addiction
Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease
A disintegrin and metalloproteinase 10 (ADAM10), a disintegrin and metalloproteinase that resides in the postsynaptic densities (PSDs) of excitatory synapses, has previously been shown to limit beta-amyloid peptide (A beta) formation in Alzheimer's disease (AD). ADAM 10 also plays a critical role in regulating functional membrane proteins at the synapse. Using human hippocampal homogenates, we found that ADAM10 removal from the plasma membrane was mediated by clathrin-dependent endocytosis. Additionally, we identified the clathrin adaptor AP2 as an interacting partner of a previously uncharacterized atypical binding motif in the ADAM10 C-terminal domain. This domain was required for ADAM10 endocytosis and modulation of its plasma membrane levels. We found that the ADAM10/AP2 association was increased in the hippo campi of AD patients compared with healthy controls. Long-term potentiation (LTP) in hippocampal neuronal cultures induced ADAM10 endocytosis through AP2 association and decreased surface ADAM10 levels and activity. Conversely, long-term depression (LTD) promoted ADAM10 synaptic membrane insertion and stimulated its activity. ADAM10 interaction with the synapse-associated protein-97 (SAP97) was necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced changes in spine morphogenesis. These data identify and characterize a mechanism controlling ADAM10 localization and activity at excitatory synapses that is relevant to AD pathogenesis
Influence of the NR3A subunit on NMDA receptor functions
Various combinations of subunits assemble to form the NMDA-type glutamate receptor (NMDAR), generating diversity in its functions. Here we review roles of the unique NMDAR subunit, NR3A, which acts in a dominant-negative manner to suppress receptor activity. NR3A-containing NMDARs display striking regional and temporal expression specificity, and, unlike most other NMDAR subtypes, they have a low conductance, are only modestly permeable to Ca(2+), and pass current at hyperpolarized potentials in the presence of magnesium. While glutamate activates triheteromeric NMDARs composed of NR1/NR2/NR3A subunits, glycine is sufficient to activate diheteromeric NR1/NR3A-containing receptors. NR3A dysfunction may contribute to neurological disorders involving NMDARs, and the subunit offers an attractive therapeutic target given its distinct pharmacological and structural properties
Building bridges through science
WOS: 000415310800007PubMed ID: 29144972Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge'' initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities.Medical Research Council [MC_UP_1202/5