ABSTRACT
Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is the most abundant kinase within excitatory synapses in the mammalian brain. It interacts with and phosphorylates a large number of synaptic proteins, including major ionotropic glutamate receptors (iGluRs) and group I metabotropic glutamate receptors (mGluRs), to constitutively and/or activity-dependently regulate trafficking, subsynaptic localization, and function of the receptors. Among iGluRs, the N-methyl-D-aspartate receptor (NMDAR) is a direct target of CaMKII. By directly binding to an intracellular C-terminal (CT) region of NMDAR GluN2B subunits, CaMKII phosphorylates a serine residue (S1303) in the GluN2B CT. CaMKII also phosphorylates a serine site (S831) in the CT of α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptors. This phosphorylation enhances channel conductance and is critical for synaptic plasticity. In addition to iGluRs, CaMKII binds to the proximal CT region of mGluR1a, which enables the kinase to phosphorylate threonine 871. Agonist stimulation of mGluR1a triggers a CaMKII-mediated negative feedback to facilitate endocytosis and desensitization of the receptor. CaMKII also binds to the mGluR5 CT. This binding seems to anchor and accumulate inactive CaMKII at synaptic sites. Active CaMKII dissociates from mGluR5 and may then bind to adjacent GluN2B to mediate the mGluR5-NMDAR coupling. Together, glutamate receptors serve as direct substrates of CaMKII. By phosphorylating these receptors, CaMKII plays a central role in controlling the number and activity of the modified receptors and determining the strength of excitatory synaptic transmission.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2 , Metabolism , Neuronal Plasticity , Phosphorylation , Receptor, Metabotropic Glutamate 5 , Metabolism , Receptors, Metabotropic Glutamate , Metabolism , Receptors, N-Methyl-D-Aspartate , Metabolism , Serine , Metabolism , Synapses , Synaptic TransmissionABSTRACT
<p><b>OBJECTIVE</b>To explore the effects of acidic fraction of Pheratima extract in an ovalbumin (OVA) induced asthma mouse model, and to provide the experimental evidences for the anti-asthmatic application of Pheratima extract with further purification and development.</p><p><b>METHOD</b>Mice model of allergic asthma was established through the OVA challenge. To investigate the inflammatory cell level and Th1/Th2 levels as well as the therapeutic effects of acidic fraction from Pheratima extract, cell count of bronchoalveolar lavage fluid (BALF) was performed to evaluate the secretion of eosinophils (EOS) cells, and IgE, IL-4, IL-5, IL-13, IFN-y levels were detected by ELISA.</p><p><b>RESULT</b>Compared with control group, the EOS count of BALF in the model group was remarkably increased (P<0.01), and IgE, IL-4, IL-5, IL-13 levels were also increased (P<0.01), while IFN-gamma decreased (P<0.01). Acidic fraction from Pheratima (S) extract and its 30% ethanol washed fraction (S30) significantly inhibited the increase of EOS count (P<0.01), decreased the IgE, IL-4, IL-5, IL-13 levels (P<0.05), and inhibited the decrease of IFN-gamma level (P<0.01).</p><p><b>CONCLUSION</b>The results indicate that inhibition of the EOS secretion and balancing of the altered Th1/Th2 levels may be important mechanisms of Pheratima's therapeutic effect in asthmatic mice model, and S30 is pharmacologically effective as evaluated with the above mentioned parameters, as a representative fraction of the Pheratima extract.</p>
Subject(s)
Animals , Male , Mice , Anti-Asthmatic Agents , Therapeutic Uses , Anti-Inflammatory Agents , Therapeutic Uses , Asthma , Drug Therapy , Metabolism , Bronchoalveolar Lavage Fluid , Chemistry , Cell Biology , Disease Models, Animal , Drugs, Chinese Herbal , Therapeutic Uses , Enzyme-Linked Immunosorbent Assay , Immunoglobulin E , Metabolism , Interleukin-13 , Metabolism , Interleukin-4 , Metabolism , Interleukin-5 , Metabolism , Mice, Inbred BALB C , OvalbuminABSTRACT
<p><b>OBJECTIVE</b>To study the proportion and mechanism of relieving asthma of drug partnership comprising herbal Ephedrae & Pheretima.</p><p><b>METHOD</b>To study relaxant effect on 10 micromol x L(-1) carbachol (CCh) and 10 micromol x L(-1) histamine (His) precontracted isolated tracheal rings and lowering effect on short-circuit current (Isc) increase induced by 10 micromol x L(-1) CCh with 3 proportions of 1:1, 1:3, 1:9 extract.</p><p><b>RESULT</b>1:3 proportions dose-dependently relaxed CCh-precontracted isolated tracheal rings, IC50 of 1:1, 1:3 is 7.5, 15 mg x mL(-1) respectively, 1:9 could not produce 50% inhibition effect on CCh-evoked contraction; 3 proportions also dose-dependently relaxed His-precontracted isolated tracheal rings, IC50 of 1:9, 1:3 and 1:1 is 0.19, 0.61, 1.8 mg x mL(-1) respectively. On the other hand,the orders potency of the decrease effect on CCh-evoked short circuit current increase is 1:3 > 1:1 > 1:9. The difference is not significant (P < 0.05).</p><p><b>CONCLUSION</b>Herbal Ephedrae & Pheretima had tracheal muscle relaxant and epithelium ion secretion inhibition effect, its mechanism of relieving asthma involved anti-CCh and anti-His effect 1:3 was the most appropriate dosage ratio in the anti-asthmatic drug partnership.</p>