SHP2 regulates GluA2 tyrosine phosphorylation required for AMPA receptor endocytosis and mGluR-LTD.

Posttranslational modifications regulate the properties and abundance of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that mediate fast excitatory synaptic transmission and synaptic plasticity in the central nervous system. During long-term depression (LTD), protein tyrosine phosphatases (PTPs) dephosphorylate tyrosine residues in the C-terminal tail of AMPA receptor GluA2 subunit, which is essential for GluA2 endocytosis and group I metabotropic glutamate receptor (mGluR)-dependent LTD. However, as a selective downstream effector of mGluRs, the mGluR-dependent PTP responsible for GluA2 tyrosine dephosphorylation remains elusive at Schaffer collateral (SC)-CA1 synapses. In the present study, we find that mGluR5 stimulation activates Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) by increasing phospho-Y542 levels in SHP2. Under steady-state conditions, SHP2 plays a protective role in stabilizing phospho-Y869 of GluA2 by directly interacting with GluA2 phosphorylated at Y869, without affecting GluA2 phospho-Y876 levels. Upon mGluR5 stimulation, SHP2 dephosphorylates GluA2 at Y869 and Y876, resulting in GluA2 endocytosis and mGluR-LTD. Our results establish SHP2 as a downstream effector of mGluR5 and indicate a dual action of SHP2 in regulating GluA2 tyrosine phosphorylation and function. Given the implications of mGluR5 and SHP2 in synaptic pathophysiology, we propose SHP2 as a promising therapeutic target for neurodevelopmental and autism spectrum disorders.

Deneddylating enzyme SENP8 regulates neuronal development.

Neddylation is a cellular process in which the neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) is conjugated to the lysine residue of target proteins via serial enzymatic cascades. Recently, it has been demonstrated that neddylation is required for synaptic clustering of metabotropic glutamate receptor 7 (mGlu7) and postsynaptic density protein 95 (PSD-95), and the inhibition of neddylation impairs neurite outgrowth and excitatory synaptic maturation. Similar to the balanced role of deubiquitylating enzymes (DUBs) in the ubiquitination process, we hypothesized that deneddylating enzymes can regulate neuronal development by counteracting the process of neddylation. We find that the SUMO peptidase family member, NEDD8 specific (SENP8) acts as a key neuronal deneddylase targeting the global neuronal substrates in primary rat cultured neurons. We demonstrate that SENP8 expression levels are developmentally regulated, peaking around the first postnatal week and gradually diminishing in mature brain and neurons. We find that SENP8 negatively regulates neurite outgrowth through multiple pathways, including actin dynamics, Wnt/ß-catenin signaling, and autophagic processes. Alterations in neurite outgrowth by SENP8 subsequently result in the impairment of excitatory synapse maturation. Our data indicate that SENP8 plays an essential role in neuronal development and is a promising therapeutic target for neurodevelopmental disorders.

Tunable Radiative Cooling by Mechanochromic Electrospun Micro-Nanofiber Matrix.

Radiative thermoregulation has been regarded as an energy-efficient method for thermal management. In this study, the development of a mechanoresponsive polydimethylsiloxane (PDMS) micro-nanofiber matrix capable of both sub-ambient radiative cooling and solar heating is presented, achieved through a core-shell electrospinning technique. The electrospun PDMS micro-nanofibers, with diameters comparable to the solar wavelengths, exhibit excellent solar reflectivity (≈93%) while preserving its pristine high infrared (IR) emissivity. As a result, the electrospun PDMS radiative cooler (EPRC) successfully demonstrated sub-ambient radiative cooling performance (≈3.8°C) during the daytime. Furthermore, the exceptional resilient property of PDMS facilitated the reversible alteration of the structural morphology created by the fiber-based matrix under mechanical force, resulting in the modulation of solar reflectivity (≈80%). The precise modulation of solar reflectivity enabled reversibly switchable multi-step radiative thermoregulation, offering enhanced flexibility in addressing varying thermal environments even in maintaining the desired temperature. The findings of this work offer a promising approach toward dynamic radiative thermoregulation, which holds significant potential for addressing global climate change concerns and energy shortage.

Pathogenic GRM7 Mutations Associated with Neurodevelopmental Disorders Impair Axon Outgrowth and Presynaptic Terminal Development.

Metabotropic glutamate receptor 7 (mGlu7) is an inhibitory heterotrimeric G-protein-coupled receptor that modulates neurotransmitter release and synaptic plasticity at presynaptic terminals in the mammalian central nervous system. Recent studies have shown that rare mutations in glutamate receptors and synaptic scaffold proteins are associated with neurodevelopmental disorders (NDDs). However, the role of presynaptic mGlu7 in the pathogenesis of NDDs remains largely unknown. Recent whole-exome sequencing (WES) studies in families with NDDs have revealed that several missense mutations (c.1865G>A:p.R622Q; c.461T>C:p.I154T; c.1972C>T:p.R658W and c.2024C>A:p.T675K) or a nonsense mutation (c.1757G>A:p.W586X) in the GRM7 gene may be linked to NDDs. In the present study, we investigated the mechanistic links between GRM7 point mutations and NDD pathology. We find that the pathogenic GRM7 I154T and R658W/T675K mutations lead to the degradation of the mGlu7 protein. In particular, the GRM7 R658W/T675K mutation results in a lack of surface mGlu7 expression in heterologous cells and cultured neurons isolated from male and female rat embryos. We demonstrate that the expression of mGlu7 variants or exposure to mGlu7 antagonists impairs axon outgrowth through the mitogen-activated protein kinase (MAPK)-cAMP-protein kinase A (PKA) signaling pathway during early neuronal development, which subsequently leads to a decrease in the number of presynaptic terminals in mature neurons. Treatment with an mGlu7 agonist restores the pathologic phenotypes caused by mGlu7 I154T but not by mGlu7 R658W/T675K because of its lack of neuronal surface expression. These findings provide evidence that stable neuronal surface expression of mGlu7 is essential for neural development and that mGlu7 is a promising therapeutic target for NDDs.SIGNIFICANCE STATEMENT Neurodevelopmental disorders (NDDs) affect brain development and function by multiple etiologies. Metabotropic glutamate receptor 7 (mGlu7) is a receptor that controls excitatory neurotransmission and synaptic plasticity. Since accumulating evidence indicates that the GRM7 gene locus is associated with NDD risk, we analyzed the functional effects of human GRM7 variants identified in patients with NDDs. We demonstrate that stable neuronal surface expression of mGlu7 is essential for axon outgrowth and presynaptic terminal development in neurons. We found that mitogen-activated protein kinase (MAPK)-cAMP-protein kinase A (PKA) signaling and subsequent cytoskeletal dynamics are defective because of the degradation of mGlu7 variants. Finally, we show that the defects caused by mGlu7 I154T can be reversed by agonists, providing the rationale for proposing mGlu7 as a potential therapeutic target for NDDs.

N-linked glycosylation of the mGlu7 receptor regulates the forward trafficking and transsynaptic interaction with Elfn1.

Metabotropic glutamate receptor 7 (mGlu7) regulates neurotransmitter release at the presynaptic active zone in the mammalian brain. The regulation of mGlu7 trafficking into and out of the plasma membrane by binding proteins within the C-terminal region of mGlu7 governs the bidirectional synaptic plasticity. However, the functional importance of the extracellular domain of mGlu7 has not yet been characterized. N-glycosylation is an abundant posttranslational modification that plays crucial roles in protein folding and forward trafficking, but the role of N-glycosylation in mGlu7 function remains unknown. In this study, we find that mGlu7 is N-glycosylated at four asparagine residues in heterologous cells and rat cultured neurons. We demonstrate that N-glycosylation is essential for forward transport and surface expression of mGlu7. Deglycosylated mGlu7 is retained in the ER, obstructing expression on the cell surface, and is degraded through the autophagolysosomal degradation pathway. In addition, we identify the binding domain of mGlu7 to Elfn1, a transsynaptic adhesion protein. We find that N-glycosylation of mGlu7 promotes its interaction with Elfn1, thereby enabling proper localization and stable surface expression of mGlu7 at the presynaptic active zone. These findings provide evidence that N-glycans act to modulate the surface expression, stability, and function of mGlu7.

The epidemiology of male lower urinary tract symptoms associated with benign prostatic hyperplasia: Results of 20 years of Korean community care and surveys.

PURPOSE: To investigate the prevalence of lower urinary tract symptoms/benign prostatic hyperplasia in a Korean population. MATERIALS AND METHODS: The Korean Prostate & Voiding Health Association provided free prostate-related community health care and conducted surveys in all regions of Korea from 2001 to 2022 with the cooperation of local government public health centers. A total of 72,068 males older than 50 were surveyed and analyzed. History taking, International Prostate Symptom Score (IPSS), transrectal ultrasonography, prostate-specific antigen (PSA) testing, uroflowmetry, and urine volume testing were performed. RESULTS: The mean prostate volumes in males in their 50s, 60s, 70s, and 80s or above were 24.7 g, 27.7 g, 31 g, and 33.7 g, respectively. The proportion of males with high PSA greater than 3 ng/mL was 3.8% among males in their 50s, 7.7% among males in their 60s, 13.1% among males in their 70s, and 17.9% among males 80 years of age or older. The mean IPSS total scores in males in their 50s, 60s, 70s, and 80s or above were 10.7, 12.7, 14.5, and 16, respectively. Severe symptoms were reported by 27.3% of males, whereas 51.7% reported moderate symptoms. The mean Qmax in males in their 50s, 60s, 70s, and 80s or above were 20 mL/s, 17.4 mL/s, 15.4 mL/s, and 13.8 mL/s, respectively. CONCLUSIONS: In this population-based study, mean prostate volume, IPSS, PSA, and Qmax were 30.6±15.1 g, 14.8±8.2, 1.9±4.7 ng/mL, and 15.6±6.5 mL/s, respectively. Aging was significantly associated with increased prostate volume, PSA levels, and IPSS scores, and with decreased Qmax and urine volume.

Contribution of genetic variation rs266882 to prostate-specific antigen levels in healthy controls with serum PSA below 2.0 ng/ml.

We evaluated the impact of genetic variation in the prostate-specific antigen (PSA) gene (rs266882) on serum PSA levels in healthy men as well as risk factors for benign prostate hypertrophy (BPH) and prostate cancer. The study population comprised 91 men with PSA levels below 2.0 ng/ml as healthy controls, 78 men with PSA 2-10 ng/ml as a BPH group, and 128 prostate cancer patients, all in Korea. DNA was amplified by polymerase chain reaction and the product was sequenced. We found that PSA levels were associated with a G/A polymorphism only in healthy controls. The transition, however, was not associated with PSA levels of BPH and cancer patients, nor was it a risk factor. In conclusion, this genetic factor is important for determining serum PSA levels in the naive group, whereas the disruption of prostatic architecture in BPH or prostate cancer may be a major determining factor for PSA levels.

Neddylation is required for presynaptic clustering of mGlu7 and maturation of presynaptic terminals.

Neddylation is a posttranslational modification in which NEDD8 is conjugated to a target substrate by cellular processes similar to those involved in ubiquitination. Recent studies have identified PSD-95 and cofilin as substrates for neddylation in the brain and have shown that neddylation modulates the maturation and stability of dendritic spines in developing neurons. However, the precise substrates and functional consequences of neddylation at presynaptic terminals remain elusive. Here, we provide evidence that the mGlu7 receptor is a target of neddylation in heterologous cells and rat primary cultured neurons. We found that mGlu7 neddylation is reduced by agonist treatment and is required for the clustering of mGlu7 in the presynaptic active zone. In addition, we observed that neddylation is not required for the endocytosis of mGlu7, but it facilitates the ubiquitination of mGlu7 and stabilizes mGlu7 protein expression. Finally, we demonstrate that neddylation is necessary for the maturation of excitatory presynaptic terminals, providing a key role for neddylation in synaptic function.

The pathogenic S688Y mutation in the ligand-binding domain of the GluN1 subunit regulates the properties of NMDA receptors.

Although numerous pathogenic mutations have been identified in various subunits of N-methyl-D-aspartate receptors (NMDARs), ionotropic glutamate receptors that are central to glutamatergic neurotransmission, the functional effects of these mutations are often unknown. Here, we combined in silico modelling with microscopy, biochemistry, and electrophysiology in cultured HEK293 cells and hippocampal neurons to examine how the pathogenic missense mutation S688Y in the GluN1 NMDAR subunit affects receptor function and trafficking. We found that the S688Y mutation significantly increases the EC50 of both glycine and D-serine in GluN1/GluN2A and GluN1/GluN2B receptors, and significantly slows desensitisation of GluN1/GluN3A receptors. Moreover, the S688Y mutation reduces the surface expression of GluN3A-containing NMDARs in cultured hippocampal neurons, but does not affect the trafficking of GluN2-containing receptors. Finally, we found that the S688Y mutation reduces Ca2+ influx through NMDARs and reduces NMDA-induced excitotoxicity in cultured hippocampal neurons. These findings provide key insights into the molecular mechanisms that underlie the regulation of NMDAR subtypes containing pathogenic mutations.

Nedd4 E3 ligase and beta-arrestins regulate ubiquitination, trafficking, and stability of the mGlu7 receptor.

The metabotropic glutamate receptor 7 (mGlu7) is a class C G protein-coupled receptor that modulates excitatory neurotransmitter release at the presynaptic active zone. Although post-translational modification of cellular proteins with ubiquitin is a key molecular mechanism governing protein degradation and function, mGlu7 ubiquitination and its functional consequences have not been elucidated yet. Here, we report that Nedd4 ubiquitin E3 ligase and ß-arrestins regulate ubiquitination of mGlu7 in heterologous cells and rat neurons. Upon agonist stimulation, ß-arrestins recruit Nedd4 to mGlu7 and facilitate Nedd4-mediated ubiquitination of mGlu7. Nedd4 and ß-arrestins regulate constitutive and agonist-induced endocytosis of mGlu7 and are required for mGlu7-dependent MAPK signaling in neurons. In addition, Nedd4-mediated ubiquitination results in the degradation of mGlu7 by both the ubiquitin-proteasome system and the lysosomal degradation pathway. These findings provide a model in which Nedd4 and ß-arrestin act together as a complex to regulate mGlu7 surface expression and function at presynaptic terminals.

Tailoring near-field thermal radiation between metallo-dielectric multilayers using coupled surface plasmon polaritons.

Several experiments have shown a huge enhancement in thermal radiation over the blackbody limit when two objects are separated by nanoscale gaps. Although those measurements only demonstrated enhanced radiation between homogeneous materials, theoretical studies now focus on controlling the near-field radiation by tuning surface polaritons supported in nanomaterials. Here, we experimentally demonstrate near-field thermal radiation between metallo-dielectric multilayers at nanoscale gaps. Significant enhancement in heat transfer is achieved due to the coupling of surface plasmon polaritons (SPPs) supported at multiple metal-dielectric interfaces. This enables the metallo-dielectric multilayers at a 160-nm vacuum gap to have the same heat transfer rate as that between semi-infinite metal surfaces separated by only 75 nm. We also demonstrate that near-field thermal radiation can be readily tuned by modifying the resonance condition of coupled SPPs. This study will provide a new direction for exploiting surface-polariton-mediated near-field thermal radiation between planar structures.

The 2nd conference on Asian trends in prostate cancer hormone therapy.

Among the aims of the 2nd Conference on Asian Trends in Prostate Cancer Hormone Therapy, Hong Kong, December 7-8, 2002, was to lay the groundwork for eventually having cooperative or collaborative studies of prostate cancer specifically in Asian patients. The conference was divided into 2 sessions. In the first session, entitled "Current Status of Therapy for Prostate Cancer in Asian Countries," the results of analysis of 100 patients with prostate cancer enrolled in the Patients Registration System is each of the 6 participating Asian countries were discussed. The Patients Registration System is a database template established by the Japanese Urological Association that allows physicians to compare prostate cancer therapy in the different Asian countries. Session 2 was devoted to a "Roundtable Discussion on the Establishment of Asian Guidelines for Prostate Cancer." This session included 2 lively discussions, on whether Asian physicians can apply Western clinical data to Asian patients, and the need for Asian clinical data and developing clinical trials in the region, respectively.