Glutamate is the major excitatory neurotransmitter in the mammalian CNS and acts on both ionotropic and metabotropic glutamate receptors (mGluRs). The mGluRs are widely distributed in the CNS and modulate a variety of neuronal processes, including neurotransmitter release and ion channel function. In hippocampus and cortex, mGluR5 is highly expressed and plays an important role in the regulation of synaptic plasticity. Calmodulin (CaM) binding dynamically regulates mGluR5 surface expression; however, the mechanisms linking CaM to mGluR5 trafficking are not clear. Recent studies showed that CaM binding to mGluR7 regulates its trafficking in a phosphorylation-dependent manner by disrupting the binding of protein interacting with C kinase 1. The E3 ligase seven in absentia homolog (Siah)-1A binds to mGluR5 and competes with CaM binding, making it an intriguing molecule to regulate phosphorylation-dependent trafficking of mGluR5. In the present study, we find that CaM competes with Siah-1A for mGluR5 binding in a phosphorylation-dependent manner in rat hippocampal neurons. Specifically, phosphorylation of mGluR5 S901 favors Siah-1A binding by displacing CaM. We identified critical residues regulating Siah-1A binding to mGluR5 and showed that binding is essential for the Siah-1A effects on mGluR5 trafficking. Siah-1A binding decreases mGluR5 surface expression and increases endosomal trafficking and lysosomal degradation of mGluR5. Thus CaM-regulated Siah-1A binding to mGluR5 dynamically regulates mGluR5 trafficking. These findings support a conserved role for CaM in regulating mGluR trafficking by PKC-dependent regulation of receptor-binding proteins.
Abstract Background: Eosinophilic gastroenteritis (EGE), a rare disorder of unknown etiology, is characterized by eosinophilic infiltration of the gastrointestinal tract in the absence of secondary causes for eosinophilia. EGE has nonspecific symptoms, but abdominal pain, nausea, and vomiting are the most common presenting symptoms. Eosinophilic ascites is a very unusual presentation. Case presentation: A 38-year-old women at 11 weeks of gestation presented with nausea, diarrhea, and abdominal pain. Magnetic resonance imaging revealed diffuse bowel wall thickening and a small amount of ascites. Despite antibiotic treatment, her symptoms were persistent and she developed marked abdominal distension and weight gain despite antibiotic treatment. Her blood eosinophil count was high, and ultrasonography showed large ascites. Diagnostic paracentesis revealed significant eosinophilia. She completely recovered with steroid treatment and delivered a healthy baby without any complications. Conclusions: To our knowledge, this is the first case of EGE presenting with ascites during pregnancy. The serosal EGE is very rare type of EGE, but it can occur during pregnancy. The augmented Th2 immunity during pregnancy may be related with EGE.
γ-aminobutyric acid (GABA)-A receptor–mediated neural transmission is important to promote practice-dependent plasticity after brain injury. This study investigated alterations in GABA-A receptor binding and functional and anatomic connectivity within the motor cortex in children with cerebral palsy (CP). Methods: We conducted 18F-fluoroflumazenil PET on children with hemiplegic CP to investigate whether in vivo GABA-A receptor binding is altered in the ipsilateral or contralateral hemisphere of the lesion site. To evaluate changes in the GABA-A receptor subunit after prenatal brain injury, we performed GABA-A receptor immunohistochemistry using rat pups with a diffuse hypoxic ischemic insult. We also performed diffusion tensor MR imaging and resting-state functional MR imaging on the same children with hemiplegic CP to investigate alterations in anatomic and functional connectivity at the motor cortex with increased GABA-A receptor binding. Results: In children with hemiplegic CP, the 18F-fluoroflumazenil binding potential was increased within the ipsilateral motor cortex. GABA-A receptors with the α1 subunit were highly expressed exclusively within cortical layers III, IV, and VI of the motor cortex in rat pups. The motor cortex with increased GABA-A receptor binding in children with hemiplegic CP had reduced thalamocortical and corticocortical connectivity, which might be linked to increased GABA-A receptor distribution in cortical layers in rats. Conclusion: Increased expression of the GABA-A receptor α1 subunit within the ipsilateral motor cortex may be an important adaptive mechanism after prenatal brain injury in children with CP but may be associated with improper functional connectivity after birth and have adverse effects on the development of motor plasticity.
Objective: This study examined the hypothesis that endocrine disrupting chemicals (EDC) are associated with premature birth (PTB). Di-2-ethylhexyl phthalate (DEHP) and bisphenol A (BPA) are best known as endocrine disruptors. Although they are known to be linked to the pathogenesis of PTB, the molecular and cellular mechanisms have yet to be fully understood.
Methods: Five-week-old, virgin female ICR mice were administered a bolus of 100ul sunflower seed oil (100%), DEHP, and BPA by intraperitoneal injection every three days for three weeks. Formalin-fixed paraffin uterine sections were stained with H&E. Protein and RNA were extracted from uterus using protein extraction solution and Tri-RNA reagent, respectively. Data analysis was conducted by using western blot and quantitative real-time polymerase chain reaction (qRT-PCR).
Results: In the group that treated with DEHP and BPA respectively, the expression of cyclooxygenase-2 (COX-2), oxytocin receptor (OTR), and connexin 43 (CX-43) related to the onset of labor pain and delivery were obviously increased. These group also showed a significant increase in the mRNA levels of the pro-inflammatory cytokines tumor necrosis factor (TNF)-, interleukin (IL)-1, and IL-6.
Conclusion: These results support that DEHP and BPA activate inflammatory signals and induce the expression of the uterine activation proteins. Together, this findings may provide insight into the association between EDC exposure and obstetrical complications.
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