Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of opioid receptors in modulating respiratory activity was investigated in in vitro brainstem preparations of adult lampreys by bath application of agonists and antagonists. The vagal motor output was used to monitor respiratory activity. Neuronal recordings were also performed to characterize the rostrolateral trigeminal region that has been suggested to be critical for respiratory rhythmogenesis. Microinjections of the micro-opioid receptor agonist [d-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) were also made into this region and at different locations within the brainstem. Bath application of DAMGO (0.5-2 microM) caused marked decreases in respiratory frequency up to complete apnea. Bath application of the delta-opioid receptor agonist [d-Pen(2,5)]-enkephalin (DPDPE) at 10-40 microM induced less pronounced depressant respiratory effects, while no changes in respiratory activity were induced by the kappa-opioid receptor agonist trans-(1S,2S)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide (U50488) at 10-40 microM. Bath application of the opioid receptor antagonists naloxone and naltrindole did not affect baseline respiratory activity, but prevented agonist-induced effects. DAMGO microinjections (1 mM; 0.5-1 nl) at sites rostrolateral to the trigeminal motor nucleus, where respiration-related neuronal activity was recorded, abolished the respiratory rhythm. The results show that opioids may have an important role in the lamprey respiratory network and that micro-opioid receptor activation is the most effective in causing respiratory depression. They also indicate that endogenous opioids are not required for the generation of baseline respiratory activity. Apneic responses induced by DAMGO microinjections support the hypothesis that a specific opioid-sensitive region rostrolateral to the trigeminal motor nucleus, that we have termed the paratrigeminal respiratory group (pTRG), likely has a pivotal role in respiratory rhythmogenesis. Since the lamprey diverged from the main vertebrate line around 450 million years ago, our results also imply that the inhibitory role of opioids on respiration is present at an early stage of vertebrate evolution.
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PMID:Opioid-induced depression in the lamprey respiratory network. 1794 22

Src tyrosine kinases (TKs) are signaling proteins involved in cell signaling pathways toward cytoskeletal, membrane and nuclear targets. In the present study, using a selective Src TK inhibitor, PP1, we investigated the roles of Src TKs in the key pulmonary responses, NF-kappaB activation, and integrin signaling during acute lung injury in BALB/C mice intratracheally treated with LPS. LPS resulted in c-Src phosphorylation in lung tissue and the phospho-c-Src was predominantly localized in recruited neutrophils and alveolar macrophages. PP1 inhibited LPS-induced increases in total protein content in bronchoalveolar lavage fluid, neutrophil recruitment, and increases in the production or activity of TNF-alpha and matrix metalloproteinase-9. PP1 also blocked LPS-induced NF-kappaB activation, and phosphorylation and degradation of IkappaB-alpha. The inhibition of NF-kappaB activation by PP1 correlated with a depression of LPS-induced integrin signaling, which included increases in the phosphorylations of integrin beta(3), and of the focal adhesion kinase (FAK) family members, FAK and Pyk2, in lung tissue, and reductions in the fibrinogen-binding activity of alveolar macrophages. Moreover, treatment with anti-alpha(v), anti-beta(3), or Arg-Gly-Asp-Ser (RGDS), inhibited LPS-induced NF-kappaB activation. Taken together, our findings suggest that Src TKs play a critical role in LPS-induced activations of NF-kappaB and integrin (alpha(v)beta(3)) signaling during acute lung injury. Therefore, Src TK inhibition may provide a potential means of ameliorating inflammatory cascade-associated lung injury.
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PMID:Src tyrosine kinases mediate activations of NF-kappaB and integrin signal during lipopolysaccharide-induced acute lung injury. 1798 91

Glutamate is a major neurotransmitter in the central nervous system, and abnormal glutamate neurotransmission has been implicated in many neurological disorders, including schizophrenia, Alzheimer's disease, Parkinson's disease, addiction, anxiety, depression, epilepsy, and pain. Metabotropic glutamate receptors (mGluRs) activate intracellular signaling cascades in a G protein-dependent manner, which offer the opportunity for developing drugs that regulate glutamate neurotransmission in a functionally selective manner. In the present study, we further characterize the human mGluR2 (hmGluR2) potentiator binding site by showing that the substitution of the three amino acids found to be required for hmGluR2 potentiation, specifically Ser(688), Gly(689), and Asn(735), with the homologous hmGluR3 amino acids, inactivates the positive allosteric modulator activity of several structurally unique mGluR2 potentiators. Based on the characterization of the hmGluR2 potentiator binding site, we developed a novel scintillation proximity assay that was able to discriminate between compounds that were hmGluR2-specific potentiators, and those that were active on both hmGluR2 and hmGluR3. In addition, we substituted Ser(688), Gly(689), and Asn(735) into hmGluR3 and created an active hmGluR2 allosteric modulation site on the hmGluR3 receptor.
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PMID:Transposition of three amino acids transforms the human metabotropic glutamate receptor (mGluR)-3-positive allosteric modulation site to mGluR2, and additional characterization of the mGluR2-positive allosteric modulation site. 1843 Aug 63

Opioids are broad-spectrum analgesics with potent pain-relieving qualities but also with potential adverse effects related to both short-term and long-term therapy. Researchers have attempted to alter existing opioid analgesics, utilize different routes/formulations, or combine opioid analgesics with other compounds in efforts to improve analgesia while minimizing adverse effects. Exogenous opioids, administered in efforts to achieve analgesia, work by mimicking the actions of endogenous opioids. Endogenous opioids and their receptors are located in the brain (supraspinal areas), spinal cord, and periphery. Although opioids and opioid receptors in the brain and spinal cord have received much attention over many years, peripheral endogenous opioid analgesic systems have only been extensively studied during the past decade. It has been known since 1990 that following injection into the rodent hindpaw, D-Ala(2),N-Me-Phe(4), Gly(5)-ol-enkephalin (DAMGO) [a muopioid receptor agonist] probably exerts its antinociceptive effects locally, since the doses administered are too low to have an effect in the central nervous system (CNS). This notion has been supported by the observation that the quaternary compound morphine methyliodide, which does not as readily cross the bloodbrain barrier and enter the CNS, produced antinociception following intradermal administration into the hindpaw, but not when the same dose was administered systemically (subcutaneously at a distant site). With a growing appreciation of peripheral endogenous opioids, peripheral endogenous opioid receptors, and peripheral endogenous opioid analgesic systems, investigators began growing hopeful that it may be possible to achieve adequate analgesics while avoiding unwanted central untoward adverse effects (e.g. respiratory depression, somnolence, addiction). Peripherally-acting opioids, which capitalize on peripheral endogenous opioid analgesic systems, may be one potential future strategy which may be utilized in efforts to achieve potent analgesia with minimal side effects.
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PMID:Peripherally-acting opioids. 1844 36

For ectothermic vertebrates, such as reptiles, the effects of opioid receptor subtype activation on breathing are poorly understood. On the basis of previous studies on mammals and lampreys, we hypothesized that mu- and delta-opioid receptor (MOR and DOR, respectively) activation would cause respiratory depression, whereas kappa-opioid receptor (KOR) activation would have no effect. To address this question, we measured respiration in awake, freely swimming adult red-eared slider turtles (Trachemys scripta) before and after injection with agonists for specific opioid receptors. Injection of the MOR agonist [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin acetate salt (DAMGO, 1.5 or 6.5 mg/kg) decreased ventilation (Ve) by 72 +/- 9% and 95 +/- 3%, respectively, 4.0 h after injection as a result of decreased breathing frequency and no change in tidal volume (Vt). DOR agonists, such as [d-Pen(2,5)]-enkephalin hydrate (DPDPE, 5.0 mg/kg) and [d-Ala(2),d-Leu(5)]-enkephalin acetate salt (DADLE, 6.3 mg/kg), decreased Ve by 44 +/- 10% and 89 +/- 4%, respectively, 4.0 h after injection as a result of decreased breathing frequency and no change in Vt. DADLE also increased breath duration by a maximum of 25 +/- 9% at 6.0 h after injection. The KOR agonist U-50488 (6.2 mg/kg) increased Vt by a maximum of 52 +/- 30% at 5.0 h after injection, with variable nonsignificant changes in Ve and breathing frequency. Naloxone injections (0.25-0.5 mg/kg) 1.0 h before opioid agonist injections blocked all DAMGO-dependent effects, DPDPE-dependent frequency depression, and DADLE-dependent breath duration augmentation for 2.0 h after agonist injections. These results show that MOR and DOR activation causes respiratory depression as a result of decreased breathing frequency, whereas Vt is increased after KOR activation.
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PMID:Inhibitory and excitatory effects of micro-, delta-, and kappa-opioid receptor activation on breathing in awake turtles, Trachemys scripta. 1878 38

Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. Our findings show that DCTN1 mutations, previously associated with motor neuron disease, can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.
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PMID:DCTN1 mutations in Perry syndrome. 2010 86

The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J x DBA/2J = BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.
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PMID:Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes. 1917 83

We present various molecular electronic descriptors of agonists and antagonists for Glycine(B)-iGluR-NMDA receptor with a view to identify computational measures that help differentiate between these two classes of biologically active compounds. We use as reference the glycine site in the NR1 subunit of the NMDA receptor (Glycine(B)-iGluR-NMDA). Glycine(B)-iGluR-NMDA receptor is important in learning and memory, and it is involved in various neurodegenerative diseases such as Alzheimer, Parkinson, and Huntington as well as in neuropathies such as schizophrenia and depression. We carried out quantum calculations at two levels, (1) B3LYP Density Functional (6-311G**), and (2) PM3 Hamiltonian for 168 molecules, of which 22 are agonists and 146 are antagonists. Regardless of the quantum mechanical level used we found a consistent signature of agonists versus antagonist action, the energy of the lowest unoccupied molecular orbital (LUMO). Effective differentiation of agonists and antagonists by a single molecular descriptor is seldom seen. We present a plausible electronic structure argument to rationalize these results.
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PMID:Molecular orbital differentiation of agonist and antagonist activity in the GlycineB-iGluR-NMDA receptor. 1924 63

MIF-1 (Pro-Leu-Gly-NH(2)) has potent therapeutic effects in depression and Parkinson's disease, but its CNS sites of production are not yet clear. In this study, the concentration of MIF-1 in different brain regions was measured by the multiple reaction monitoring technique on a 4000 QTRAP mass spectrometer. The limit of quantification was 300 fg of MIF-1, and limit of detection was 60 fg. The low molecular weight fractions of tissue homogenates from different regions of mouse brain were analyzed. The concentration of MIF-1 ranged from 22+/-3 fg/microg protein in cerebral cortex to 930+/-60 fg/microg protein in the hypothalamus. Moderate concentrations were also detected in all other regions tested, including the striatum, thalamus, and hippocampus. By incubation of stable isotope-labeled oxytocin with tissue preparations, it was also confirmed that oxytocin at least partially contributed to the production of MIF-1 in the hypothalamus by action of peptidases. Regional differences were also found. The results are the first to show the ultrasensitive quantification of MIF-1 in different brain regions, and support the neuromodulatory actions of MIF-1 in the striatum.
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PMID:Mass spectrometric quantification of MIF-1 in mouse brain by multiple reaction monitoring. 1954 Apr 26

The objectives of this study were to determine the effects of dietary glycyl-glutamine (Gly-Gln) on postweaning growth, small intestinal morphology, and immune response of stressed or nonstressed piglets. Pigs (n = 144; initially 4.49 kg and 14 d of age) were randomly allocated to 24 pens (6 pigs/pen) in an environmentally controlled nursery and assigned to Escherichia coli lipopolysaccharide (LPS) challenge (PBS vs. LPS) and Gly-Gln supplementation (0 vs. 0.15%) in a 2 x 2 factorial arrangement of treatments with 6 pens/treatment. The LPS was the stress-inducing agent, and it was injected on d 7 and 14 of the 21-d experiment. Inflammatory challenge with LPS reduced ADG (P < 0.05) and tended to reduce ADFI (P = 0.06) of piglets from d 7 to 21 of the experiment. Supplementation of Gly-Gln increased ADG and G:F from d 0 to 21 (P < 0.05). On d 21 (1 wk after the second LPS injection), there was an LPS challenge x diet Gly-Gln interaction for ADFI (P < 0.05), but it was difficult to ascertain whether Gly-Gln increased ADFI. A trend for an LPS challenge x diet Gly-Gln interaction was observed for ADG (P = 0.07). There were no differences in lymphocyte proliferation among treatments. The LPS challenge increased crypt depth (CD) of the duodenum and decreased the ratio of villus height (VH) to CD of the ileum (P < 0.05) on d 14 (1 wk after the first LPS injection), whereas dietary supplementation of Gly-Gln increased VH of the ileum and VH:CD of the duodenum (P < 0.05). The concentration of peripheral blood IL-1beta was increased by injection of LPS (P < 0.05) and was decreased by dietary Gly-Gln supplementation during the experimental period (P < 0.05); however, there was no interaction of LPS challenge x Gly-Gln addition for IL-1beta concentration. Concentrations of peripheral blood IL-2 tended to increase at d 14 (P = 0.09) and soluble IL-2 receptor tended to decrease at d 7 (P = 0.06) in piglets supplemented with Gly-Gln; therefore, the peripheral blood IL-2/soluble IL-2 receptor system tended to favor the secretion of IL-2 during the first 2 wk of the experiment. In conclusion, considerable suppression of growth and immune function occurred in early weaning piglets challenged with LPS, and such depression could be alleviated by dietary Gly-Gln supplementation independent of the LPS challenge.
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PMID:Effects of dietary glycyl-glutamine on growth performance, small intestinal integrity, and immune responses of weaning piglets challenged with lipopolysaccharide. 1971 85


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