NMDA receptors are tetrameric ligand-gated ion channels comprised of GluN1, GluN2, and GluN3 subunits. Two different GluN2 subunits have been identified in most NMDA receptor-expressing cells, and ...the majority of native receptors are triheteromers containing two GluN1 and two different GluN2. In contrast to diheteromeric NMDA receptors, little is known about the function of triheteromers. We developed a method to provide selective cell-surface expression of recombinant GluN1/GluN2A/GluN2B triheteromers and compared properties of these receptors with those of GluN1/GluN2A and GluN1/GluN2B diheteromers. We show that glutamate deactivation of triheteromers is distinct from those of GluN1/GluN2A and GluN1/GluN2B and reveal modulation of triheteromers by subunit-selective antagonists ifenprodil, CP-101,606, TCN-201, and extracellular Zn2+. Furthermore, kinetic measurements suggest variation in the ifenprodil binding site of triheteromers compared to GluN1/GluN2B diheteromers. This work provides insight into the distinct properties of GluN1/GluN2A/GluN2B triheteromers, which are presumably the most abundant NMDA receptors in the adult forebrain.
•A method to selectively express recombinant GluN1/GluN2A/GluN2B triheteromers•GluN1/GluN2A/GluN2B triheteromers have distinct pharmacological properties•Variation in the ifenprodil binding site of triheteromers compared to GluN1/GluN2B•GluN1/GluN2A/GluN2B triheteromers have distinct glutamate deactivation
Hansen et al. develop a method to study triheteromeric NMDA receptors and provide a comprehensive assessment of properties relevant for synaptic signaling and therapeutic manipulation of the most abundant NMDA receptor subtype in the adult hippocampus and cortex.
NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca
-permeable component of excitatory neurotransmission in the central nervous system (CNS). They are expressed throughout ...the CNS and play key physiological roles in synaptic function, such as synaptic plasticity, learning, and memory. NMDA receptors are also implicated in the pathophysiology of several CNS disorders and more recently have been identified as a locus for disease-associated genomic variation. NMDA receptors exist as a diverse array of subtypes formed by variation in assembly of seven subunits (GluN1, GluN2A-D, and GluN3A-B) into tetrameric receptor complexes. These NMDA receptor subtypes show unique structural features that account for their distinct functional and pharmacological properties allowing precise tuning of their physiological roles. Here, we review the relationship between NMDA receptor structure and function with an emphasis on emerging atomic resolution structures, which begin to explain unique features of this receptor.
Abstract
Detections and non-detections of Lyman alpha (Lyα) emission from z > 6 galaxies (<1 Gyr after the big bang) can be used to measure the timeline of cosmic reionization. Of key interest to ...measuring reionization’s mid-stages, but also increasing observational challenge, are observations at z > 7, where Lyα redshifts to near infra-red wavelengths. Here we present a search for z > 7.2 Lyα emission in 53 intrinsically faint Lyman Break Galaxy candidates, gravitationally lensed by massive galaxy clusters, in the KMOS Lens-Amplified Spectroscopic Survey (KLASS). With integration times of ∼7–10 h, we detect no Lyα emission with signal-to-noise ratio (S/N) > 5 in our sample. We determine our observations to be 80 per cent complete for 5σ spatially and spectrally unresolved emission lines with integrated line flux >5.7 × 10−18 erg s−1 cm−2. We define a photometrically selected sub-sample of 29 targets at z = 7.9 ± 0.6, with a median 5σ Lyα EW limit of 58 Å. We perform a Bayesian inference of the average intergalactic medium (IGM) neutral hydrogen fraction using their spectra. Our inference accounts for the wavelength sensitivity and incomplete redshift coverage of our observations, and the photometric redshift probability distribution of each target. These observations, combined with samples from the literature, enable us to place a lower limit on the average IGM neutral hydrogen fraction of $\gt 0.76 \,\, (68{{\ \rm per\ cent}}), \,\, \gt 0.46 \,\, (95{{\ \rm per\ cent}})$ at z ∼ 8, providing further evidence of rapid reionization at z ∼ 6–8. We show that this is consistent with reionization history models extending the galaxy luminosity function to $M_ \rm {\small UV}\lesssim -12$, with low ionizing photon escape fractions, $f_\textrm{esc} \lesssim 15{{\ \rm per\ cent}}$.
We investigate the intracluster light (ICL) in the six Hubble Frontier Field clusters at 0.3 < z < 0.6 . We employ a new method, which is free from any functional form of the ICL profile, and exploit ...the unprecedented depth of this Hubble Space Telescope imaging to map the ICL's diffuse light out to clustrocentric radii R ∼ 300 kpc ( ICL ∼ 27 mag arcsec−2). From these maps, we construct radial color and stellar mass profiles via SED fitting and find clear negative color gradients in all systems with increasing distance from the Brightest Cluster Galaxy (BCG). While this implies older/more metal-rich stellar components in the inner part of the ICL, we find that the ICL mostly consists of a 2 Gyr population, and plausibly originated with log M * M 10 cluster galaxies. Furthermore, we find that 10%-15% of the ICL's mass at large radii ( 150 kpc) lies in a younger/bluer stellar population (∼1 Gyr), a phenomenon not seen in local samples. We attribute this light to the higher fraction of star-forming/(post-)starburst galaxies in clusters at z ∼ 0.5 . Ultimately, we find the ICL's total mass to be log M * ICL M ∼ 11 -12, constituting 5%-20% of the clusters' total stellar mass, or about half of the value at z ∼ 0 . The above implies distinct formation histories for the ICL and BCGs/other massive cluster galaxies; i.e., the ICL at this epoch is still being constructed rapidly ( ∼ 40 M yr−1), while the BCGs have mostly completed their evolution. To be consistent with the ICL measurements of local massive clusters, such as Virgo, our data suggest mass acquisition mainly from quiescent cluster galaxies is the principal source of ICL material in the subsequent ∼5 Gyr of cosmic time.
Desmoid-type fibromatosis is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Currently, there is no ...established or evidence-based treatment approach available for this disease. Therefore, in 2015 the European Desmoid Working Group published a position paper giving recommendations on the treatment of this intriguing disease. Here, we present an update of this consensus approach based on professionals’ AND patients’ expertise following a round table meeting bringing together sarcoma experts from the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group with patients and patient advocates from Sarcoma PAtients EuroNet. In this paper, we focus on new findings regarding the prognostic value of mutational analysis in desmoid-type fibromatosis patients and new systemic treatment options.
The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation ...pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.
Context.
Spectroscopic surveys of massive galaxy clusters reveal the properties of faint background galaxies thanks to the magnification provided by strong gravitational lensing.
Aims.
We present a ...systematic analysis of integral-field-spectroscopy observations of 12 massive clusters, conducted with the Multi Unit Spectroscopic Explorer (MUSE). All data were taken under very good seeing conditions (∼0″.6) in effective exposure times between two and 15 h per pointing, for a total of 125 h. Our observations cover a total solid angle of ∼23 arcmin
2
in the direction of clusters, many of which were previously studied by the MAssive Clusters Survey, Frontier Fields (FFs), Grism Lens-Amplified Survey from Space and Cluster Lensing And Supernova survey with
Hubble
programmes. The achieved emission line detection limit at 5
σ
for a point source varies between (0.77–1.5) × 10
−18
erg s
−1
cm
−2
at 7000 Å.
Methods.
We present our developed strategy to reduce these observational data, detect continuum sources and line emitters in the datacubes, and determine their redshifts. We constructed robust mass models for each cluster to further confirm our redshift measurements using strong-lensing constraints, and identified a total of 312 strongly lensed sources producing 939 multiple images.
Results.
The final redshift catalogues contain more than 3300 robust redshifts, of which 40% are for cluster members and ∼30% are for lensed Lyman-
α
emitters. Fourteen percent of all sources are line emitters that are not seen in the available HST images, even at the depth of the FFs (∼29 AB). We find that the magnification distribution of the lensed sources in the high-magnification regime (
μ
= 2–25) follows the theoretical expectation of
N
(
z
) ∝
μ
−2
. The quality of this dataset, number of lensed sources, and number of strong-lensing constraints enables detailed studies of the physical properties of both the lensing cluster and the background galaxies. The full data products from this work, including the datacubes, catalogues, extracted spectra, ancillary images, and mass models, are made available to the community.
Abstract
The past decade has seen impressive progress in the detection of
z
> 7 galaxies with the Hubble Space Telescope; however, little is known about their properties. The James Webb Space ...Telescope will revolutionize the high-
z
field by providing near-IR (i.e., rest-frame optical) data of unprecedented depth and spatial resolution. Measuring galaxy quantities such as resolved stellar ages or gas metallicity gradients traditionally requires spectroscopy, as broadband imaging filters are generally too coarse to fully isolate diagnostics such as the 4000 Å (rest-frame) break, continuum emission from aged stars, and key emission lines (e.g., O
ii
, O
iii
, H
β
). However, in this paper, we show that adding NIRCam images through a strategically chosen medium-band filter to common wide-band filter sets adopted by ERS and GTO programs delivers tighter constraints on these galactic properties. To constrain the choice of filter, we perform a systematic investigation of which combinations of wide-band filters from ERS and GTO programs and single medium-band filters offer the tightest constraints on several galaxy properties at redshifts
z
∼ 7–11. We employ the JAGUAR extragalactic catalogs to construct statistical samples of physically motivated mock photometry and conduct SED-fitting procedures to evaluate the accuracy of galaxy property (and photo-
z
) recovery with a simple star formation history model. We find that adding >4.1
μ
m medium filters at comparable depth to the broadband filters can significantly improve photo-
z
s and yield close to order-of-magnitude improvements in the determination of quantities such as stellar ages, metallicities, SF-related quantities, and emission-line fluxes at
z
∼ 8. For resolved sources, the proposed approach enables the spatially resolved determination of these quantities that would be prohibitive with slit spectroscopy.
We report the first measurements with sub-kiloparsec spatial resolution of strongly inverted gas-phase metallicity gradients in two dwarf galaxies at z ∼ 2. The galaxies have stellar masses ∼109 , ...specific star formation rate ∼20 Gyr−1, and global metallicity (1/4 solar), assuming the strong-line calibrations of O iii/Hβ and O ii/Hβ from Maiolino et al. Their radial metallicity gradients are measured to be highly inverted, i.e., 0.122 0.008 and 0.111 0.017 dex kpc−1, which is hitherto unseen at such small masses in similar redshift ranges. From the Hubble Space Telescope observations of the source nebular emission and stellar continuum, we present two-dimensional spatial maps of star formation rate surface density, stellar population age, and gas fraction, which show that our galaxies are currently undergoing rapid mass assembly via disk inside-out growth. More importantly, using a simple chemical evolution model, we find that the gas fractions for different metallicity regions cannot be explained by pure gas accretion. Our spatially resolved analysis based on a more advanced gas regulator model results in a spatial map of net gaseous outflows, triggered by active central starbursts, that potentially play a significant role in shaping the spatial distribution of metallicity by effectively transporting stellar nucleosynthesis yields outwards. The relation between wind mass loading factors and stellar surface densities measured in different regions of our galaxies shows that a single type of wind mechanism, driven by either energy or momentum conservation, cannot explain the entire galaxy. These sources present a unique constraint on the effects of gas flows on the early phase of disk growth from the perspective of spatially resolved chemical evolution within individual systems.
Key points
Triheteromeric NMDA receptors contain two GluN1 and two distinct GluN2 subunits and mediate excitatory neurotransmission in the CNS.
Triheteromeric GluN1/2B/2D receptors have functional ...properties intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors.
GluN1/2B/2D receptors are more sensitive to channel blockade by ketamine and memantine compared to GluN1/2B receptors in the presence of physiological Mg2+.
GluN2B‐selective antagonists produce robust inhibition of GluN1/2B/2D receptors, and the GluN2B‐selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors.
These insights into the properties of triheteromeric GluN1/2B/2D receptors are necessary to appreciate their physiological roles in neural circuit function and the actions of therapeutic agents targeting NMDA receptors.
Triheteromeric NMDA‐type glutamate receptors that contain two GluN1 and two different GluN2 subunits contribute to excitatory neurotransmission in the adult CNS. In the present study, we report properties of the triheteromeric GluN1/2B/2D NMDA receptor subtype that is expressed in distinct neuronal populations throughout the CNS. We show that neither GluN2B, nor GluN2D dominate the functional properties of GluN1/2B/2D receptors because agonist potencies, open probability and the glutamate deactivation time course of GluN1/2B/2D receptors are intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. Furthermore, channel blockade of GluN1/2B/2D by extracellular Mg2+ is intermediate compared to GluN1/2B and GluN1/2D, although GluN1/2B/2D is more sensitive to blockade by ketamine and memantine compared to GluN1/2B in the presence of physiological Mg2+. Subunit‐selective allosteric modulators have distinct activity at GluN1/2B/2D receptors, including GluN2B‐selective antagonists, ifenprodil, EVT‐101 and CP‐101‐606, which inhibit with similar potencies but with different efficacies at GluN1/2B/2D (∼65% inhibition) compared to GluN1/2B (∼95% inhibition). Furthermore, the GluN2B‐selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors. We show that these key features of allosteric modulation of recombinant GluN1/2B/2D receptors are also observed for NMDA receptors in hippocampal interneurons but not CA1 pyramidal cells, which is consistent with the expression of GluN1/2B/2D receptors in interneurons and GluN1/2A/2B receptors in pyramidal cells. Altogether, we uncover previously unknown functional and pharmacological properties of triheteromeric GluN1/2B/2D receptors that can facilitate advances in our understanding of their physiological roles in neural circuit function and therapeutic drug actions.
Key points
Triheteromeric NMDA receptors contain two GluN1 and two distinct GluN2 subunits and mediate excitatory neurotransmission in the CNS.
Triheteromeric GluN1/2B/2D receptors have functional properties intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors.
GluN1/2B/2D receptors are more sensitive to channel blockade by ketamine and memantine compared to GluN1/2B receptors in the presence of physiological Mg2+.
GluN2B‐selective antagonists produce robust inhibition of GluN1/2B/2D receptors, and the GluN2B‐selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors.
These insights into the properties of triheteromeric GluN1/2B/2D receptors are necessary to appreciate their physiological roles in neural circuit function and the actions of therapeutic agents targeting NMDA receptors.
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