A single, low dose of the NMDA receptor antagonist ketamine produces rapid antidepressant actions in treatment-resistant depressed patients. Understanding the cellular mechanisms underlying this will lead to new therapies for treating major depression. NMDARs are heteromultimeric complexes formed through association of two GluN1 and two GluN2 subunits. We show that in vivo deletion of GluN2B, only from principal cortical neurons, mimics and occludes ketamine's actions on depression-like behavior and excitatory synaptic transmission. Furthermore, ketamine-induced increases in mTOR activation and synaptic protein synthesis were mimicked and occluded in 2BΔCtx mice. We show here that cortical GluN2B-containing NMDARs are uniquely activated by ambient glutamate to regulate levels of excitatory synaptic transmission. Together these data predict a novel cellular mechanism that explains ketamine's rapid antidepressant actions. In this model, basal glutamatergic neurotransmission sensed by cortical GluN2B-containing NMDARs regulates excitatory synaptic strength in PFC determining basal levels of depression-like behavior.DOI: http://dx.doi.org/10.7554/eLife.03581.001

The subunit composition of N-methyl D-aspartate receptors (NMDARs) is tightly regulated during cortical development. NMDARs are initially dominated by GluN2B (NR2B), whereas GluN2A (NR2A) incorporation increases after birth. The function of GluN2B-containing NMDARs during development, however, is incompletely understood. We generated a mouse in which we genetically replaced GluN2B with GluN2A (2B→2A). Although this manipulation restored NMDAR-mediated currents at glutamatergic synapses, it did not rescue GluN2B loss of function. Protein translation-dependent homeostatic synaptic plasticity is occluded in the absence of GluN2B, and AMPA receptor contribution is enriched at excitatory cortical synapses. Our experiments indicate that specificity of GluN2B-mediated signaling is due to its unique interaction with the protein effector alpha calcium-calmodulin kinase II and the regulation of the mTOR pathway. Homozygous 2B→2A mice exhibited high rates of lethality, suppressed feeding, and depressed social exploratory behavior. These experiments indicate that GluN2B-containing NMDARs activate unique cellular processes that cannot be rescued by replacement with GluN2A.

The molecular mechanism underlying the post-Golgi transport of G protein-coupled receptors (GPCRs) remains poorly understood. Here we determine the role of Rab8 GTPase, which modulates vesicular protein transport between the trans-Golgi network (TGN) and the plasma membrane, in the cell surface targeting of ␣ 2B -and ␤ 2 -adrenergic receptors (AR). Transient expression of GDP-and GTP-bound Rab8 mutants and short hairpin RNA-mediated knockdown of Rab8 more potently inhibited the cell surface expression of ␣ 2B -AR than ␤ 2 -AR. The GDP-bound Rab8(T22N) mutant attenuated ERK1/2 activation by ␣ 2B -AR, but not ␤ 2 -AR, and arrested ␣ 2B -AR in the TGN compartment. Co-immunoprecipitation revealed that both ␣ 2B -AR and ␤ 2 -AR physically interacted with Rab8 and glutathione S-transferase fusion protein pulldown assays demonstrated that Rab8 interacted with the C termini of both receptors. Interestingly, mutation of the highly conserved membrane-proximal C terminus dileucine motif selectively blocked ␤ 2 -AR interaction with Rab8, whereas mutation of residues (T22N) of a chimeric ␤ 2 -AR carrying the ␣ 2B -AR C terminus was similar to ␣ 2B -AR. These data provide strong evidence indicating that Rab8 GTPase interacts with distinct motifs in the C termini of ␣ 2B -AR and ␤ 2 -AR and differentially modulates their traffic from the TGN to the cell surface.

In this work, temperature dependence of phase behaviors for the [Bmim]BF 4 + sucrose + water system was investigated. It was found that interaction of [Bmim]BF 4 with sucrose is exothermic, and lowering temperature is favorable for phase separation. In addition, a "[Bmim] (+)-induced structural changes" model was developed and used to interpret the temperature effect, whereby the salting-out effect was thought to be an entropy driving process through analysis of the structural interaction and the electrostatic interaction.

Echinacoside (ECH), a natural phenylethanoid glycoside, was first isolated from Echinacea angustifolia DC. (Compositae) sixty years ago. It was found to possess numerous pharmacologically beneficial activities for human health, especially the neuroprotective and cardiovascular effects. Although ECH showed promising potential for treatment of Parkinson’s and Alzheimer’s diseases, some important issues arose. These included the identification of active metabolites as having poor bioavailability in prototype form, the definite molecular signal pathways or targets of ECH with the above effects, and limited reliable clinical trials. Thus, it remains unresolved as to whether scientific research can reasonably make use of this natural compound. A systematic summary and knowledge of future prospects are necessary to facilitate further studies for this natural product. The present review generalizes and analyzes the current knowledge on ECH, including its broad distribution, different preparation technologies, poor pharmacokinetics and kinds of therapeutic uses, and the future perspectives of its potential application.