UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 5-HT1A receptor is implicated in depression and anxiety. This receptor couples to G(i) proteins to inhibit adenylyl cyclase (AC) activity but can stimulate AC in tissues (e.g. hippocampus) that express ACII. The role of ACII in receptor-mediated stimulation of cAMP formation was examined in HEK-293 cells transfected with the 5-HT1A receptor, which mediated inhibition of basal and G(s)-induced cAMP formation in the absence of ACII. In cells cotransfected with 5-HT1A receptor and ACII plasmids, 5-HT1A agonists induced a 1. 5-fold increase in cAMP level. Cotransfection of 5-HT1A receptor, ACII, and Galpha(i2), but not Galpha(i1), Galpha(i3), or Galpha(o), resulted in an agonist-independent 6-fold increase in the basal cAMP level, suggesting that G(i2) preferentially coupled the receptor to ACII. The 5-HT1B receptor also constitutively activated ACII. Constitutive activity of the 5-HT1A receptor was blocked by pertussis toxin and the Gbetagamma antagonist, betaCT, suggesting an important role for Gbetagamma-mediated activation of ACII. The Thr-149 --> Ala mutation in the second intracellular domain of the 5-HT1A receptor disrupted Gbetagamma-selective activation of ACII. Spontaneous 5-HT1A receptor activity was partially attenuated by 5-HT1A receptor partial agonists with anxiolytic activity (e.g. buspirone and flesinoxan) but was not altered by full agonists or antagonists. Thus, anxiolytic activity may involve inhibition of spontaneous 5-HT1A receptor activity.
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PMID:Constitutive G(i2)-dependent activation of adenylyl cyclase type II by the 5-HT1A receptor. Inhibition by anxiolytic partial agonists. 1058 18

Phenelzine (PLZ) is a non-selective monoamine oxidase (MAO) inhibitor commonly used to treat depression and panic disorder. Acute administration of PLZ produces several neurochemical changes, including an increase in brain levels of the catecholamines norepinephrine (NE) and dopamine (DA), of 5-hydroxytryptamine (5-HT), and of the amino acids alanine and gamma-aminobutyric acid (GABA). The goal of the present series of experiments was to characterize the time course of these PLZ-induced changes. Male Sprague-Dawley rats were sacrificed 6, 24, 48, 96, 168, or 336 hr after acute PLZ administration (15 or 30 mg/kg, i.p., based on free base weight). Whole brain levels of monoamines and amino acids were determined using HPLC, and MAO A and B activities were determined using a radiochemical procedure. The results indicated that PLZ changed amino acid levels 6 and 24 hr after injection, but not 48 hr later. In contrast, the effects of PLZ on MAO activity and monoamines were longer-lasting. For example, PLZ-induced increases in dopamine and 5-HT were observed 1 week after injection, and PLZ-induced inhibition of MAO activity persisted for 2 weeks. Thus, in addition to demonstrating that the effects of PLZ on MAO activity and monoamines were long-lasting, these results indicate that the effects of PLZ on MAO activity and on brain levels of monoamines and amino acids are temporally dissociated. These findings regarding the long-term effects of PLZ on neurochemistry will have considerable critical implications for the design and interpretation of behavioral studies of the acute effects of PLZ.
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PMID:Time-dependent changes in brain monoamine oxidase activity and in brain levels of monoamines and amino acids following acute administration of the antidepressant/antipanic drug phenelzine. 1073 26

Phospholamban is a regulator of the Ca(2+) affinity of the cardiac sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) and of cardiac contractility. In vitro expression studies have shown that several mutant phospholamban monomers are superinhibitory, suggesting that monomeric phospholamban is the active species. However, a phospholamban Asn(27) --> Ala (N27A) mutant, which maintained a normal pentamer to monomer ratio, was shown to act as a superinhibitor of SERCA2a Ca(2+) affinity. To determine whether the pentameric N27A mutant is superinhibitory in vivo, transgenic mice with cardiac-specific overexpression of mutant phospholamban were generated. Quantitative immunoblotting revealed a 61 +/- 6% increase in total phospholamban in mutant hearts, with 90% of the overexpressed protein being pentameric. The EC(50) value for Ca(2+) dependence of Ca(2+) uptake was 0.69 +/- 0.07 microM in mutant hearts, compared with 0.29 +/- 0.02 microM in wild-type hearts or 0. 43 +/- 0.03 microM in hearts overexpressing wild-type PLB by 2-fold. Myocytes from phospholamban N27A mutant hearts also exhibited more depressed contractile parameters than wild-type phospholamban overexpressing cells. The shortening fraction was 52%, rates of shortening and relengthening were 46% and 38% respectively, and time for 80% decay of the Ca(2+) signal was 146%, compared with wild-types (100%). Langendorff-perfused mutant hearts also demonstrated depressed contractile parameters. Furthermore, in vivo echocardiography showed a depression in the ratio of early to late diastolic transmitral velocity and a 79% prolongation of the isovolumic relaxation time. Isoproterenol stimulation did not fully relieve the depressed contractile parameters at the cellular, organ, and intact animal levels. Thus, pentameric phospholamban N27A mutant can act as a superinhibitor of the affinity of SERCA2a for Ca(2+) and of cardiac contractility in vivo.
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PMID:Cardiac-specific overexpression of a superinhibitory pentameric phospholamban mutant enhances inhibition of cardiac function in vivo. 1074 47

The study was undertaken to test the inhibitory potential on cholesterogenesis of organosulfur compounds derived from garlic. The primary rat hepatocytes maintained in Dulbecco's modified Eagle's medium were treated with [2-14C]acetate as substrate for cholesterol synthesis in the presence or absence of test compounds at 0.05 to 4.0 mmol/L. Eleven water-soluble and six lipid-soluble compounds of garlic were tested. Among water-soluble compounds, S-allyl cysteine (SAC), S-ethyl cysteine (SEC), and S-propyl cysteine (SPC) inhibited [2-14C]acetate incorporation into cholesterol in a concentration-dependent manner, achieving 42 to 55% maximal inhibition. Gamma-glutamyl-S-allyl cysteine, gamma-glutamyl-S-methyl cysteine, and gamma-glutamyl-S-propyl cysteine were less potent, exerting only 16 to 29% maximal inhibitions. Alliin, S-allyl-N-acetyl cysteine, S-allylsulfonyl alanine, and S-methyl cysteine had no effect on cholesterol synthesis. Of the lipid-soluble compounds, diallyl disulfide (DADS), diallyl trisulfide (DATS), and dipropyl disulfide (DPDS) depressed cholesterol synthesis by 10 to 25% at low concentrations (< or =0.5 mmol/L), and abolished the synthesis at high concentrations (> or =1.0 mmol/L). Diallyl sulfide, dipropyl sulfide, and methyl allyl sulfide slightly inhibited [2-14C]acetate incorporation into cholesterol only at high concentrations. The complete depression of cholesterol synthesis by DADS, DATS, and DPDS was associated with cytotoxicity as indicated by marked increase in cellular LDH release. There was no apparent increase in LDH secretion by water-soluble compounds except S-allyl mercaptocysteine, which also abolished cholesterol synthesis. Judging from maximal inhibition and IC50 (concentration required for 50% of maximal inhibition), SAC, SEC, and SPC are equally potent in inhibiting cholesterol synthesis.
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PMID:Inhibition of cholesterol biosynthesis by organosulfur compounds derived from garlic. 1075 51

A vital role for complement in adaptive humoral immunity is now beyond dispute. The crucial interaction is that between B cell and follicular dendritic cell-resident complement receptor 2 (CR2, CD21) and its Ag-associated ligands iC3b and C3dg, where the latter have been deposited as a result of classical pathway activation. Despite the obvious importance of this interaction, the location of a CR2 binding site within C3d, a proteolytic limit fragment of C3dg retaining CR2 binding activity, has not been firmly established. The recently determined x-ray structure of human C3d suggested a candidate site that was remote from the site of covalent attachment to Ag and consisted of an acidic residue-lined depression, which accordingly displays a significant electronegative surface potential. These attributes were consistent with the known ionic strength dependence of the CR2-C3d interaction and with the fact that a significant electropositive surface was apparent in a modeled structure of the C3d-binding domains of CR2. Therefore, we have performed an alanine scan of all of the residues within and immediately adjacent to the acidic pocket in C3d. By testing the mutant iC3b molecules for their ability to bind CR2, we have identified two separate clusters of residues on opposite sides of the acidic pocket, specifically E37/E39 and E160/D163/I164/E166, as being important CR2-contacting residues in C3d. Within the second cluster even single mutations cause near total loss of CR2 binding activity. Consistent with the proposed oppositely charged nature of the interface, we have also found that removal of a positive charge immediately adjacent to the acidic pocket (mutant K162A) results in a 2-fold enhancement in CR2 binding activity.
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PMID:Structure-guided identification of C3d residues essential for its binding to complement receptor 2 (CD21). 1103 90

In 70 patients (94% were a consecutive series) with angina pectoris and normal coronary angiograms, we measured cardiac exchange of lactate, glucose, free fatty acids (FFAs), glutamate, alanine, citrate, and oxygen together with coronary sinus blood flow and blood pressure in response to pacing (150 beats/min). Twelve patients had an abnormal exercise stress test; 26 developed ST depression and 46 had chest pain in response to pacing. Sixteen patients had no ST changes (exercise/ pacing) and no pain during pacing. Pacing induced an increase in cardiac carbohydrate extraction and a decrease in FFA extraction in the entire group of patients. Less than 3% of patients had significant cardiac lactate release in response to pacing, and there were no consistent differences in the cardiac metabolic or hemodynamic responses between patient groups. The pacing-induced shift from FFA to carbohydrate extraction probably reflects the cardiac response to an acute workload. A definite sign of cardiac ischemia (lactate production) was a rare finding in these patients and not confined to the demonstration of electrocardiographic signs of ischemia.
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PMID:Cardiac energy metabolism in patients with chest pain and normal coronary angiograms. 1107 99

The tertiary and quaternary structure of the lectin I from Ulex europaeus (UE-I) has been determined to 2.2 A resolution. UE-I is a dimeric metalloglycoprotein that binds the H-type 2 human blood group determinant [alpha-L-Fucalpha(1-->2)-beta-D-Galbeta(1-->4)-beta-D-Glc NAcalpha-]. Nine changes from the published amino acid sequence were necessary to account for the electron density. The quaternary structural organization of UE-I is that of the most commonly occurring legume lectin dimer. The tertiary structure of the monomeric subunits is similar to that in the conventional lectin subunit; however, some structural differences are noted. These differences include a four-stranded anti-parallel "S" sheet in UE-I versus the five-stranded S sheet in other lectin monomers. The Ala residue of the Ala-Asp cis-peptide bond present in the carbohydrate-binding site of the conventional lectin monomer is replaced with a Thr in the UE-I structure. Also, a novel disulfide bridge linking Cys115 and Cys150 is present. There are two metallic ions, one calcium and the other manganese, per subunit. N-linked oligosaccharides are at residues 23 and 111 of each subunit. One molecule of R-2-methyl-2, 4-pentanediol (R-MPD) is present in a shallow depression on the surface of each subunit. In order to examine the binding of the H-type 2 blood group determinant by UE-I, its beta-methyl glycoside (H-type 2-OMe) was docked into the binding site of R-MPD. The epitope previously identified for H-type 2-OMe by chemical mapping proved, with only minor adjustment of amino acid residues, to be complementary to the shallow cavity occupied by R-MPD in the structure. Several key interactions have been proposed between the H-type 2-OMe and UE-I.
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PMID:The 2.2 A resolution structure of the O(H) blood-group-specific lectin I from Ulex europaeus. 1109 Feb 84

In Salmonella typhimurium, formation of the cobalt-carbon bond in the biosynthetic pathway for adenosylcobalamin is catalyzed by the product of the cobA gene which encodes a protein of 196 amino acid residues. This enzyme is an ATP:co(I)rrinoid adenosyltransferase which transfers an adenosyl moiety from MgATP to a broad range of co(I)rrinoid substrates that are believed to include cobinamide, its precursor cobyric acid and probably others as yet unidentified, and hydroxocobalamin. Three X-ray structures of CobA are reported here: its substrate-free form, a complex of CobA with MgATP, and a ternary complex of CobA with MgATP and hydroxycobalamin to 2.1, 1.8, and 2.1 A resolution, respectively. These structures show that the enzyme is a homodimer. In the apo structure, the polypeptide chain extends from Arg(28) to Lys(181) and consists of an alpha/beta structure built from a six-stranded parallel beta-sheet with strand order 324516. The topology of this fold is very similar to that seen in RecA protein, helicase domain, F(1)ATPase, and adenosylcobinamide kinase/adenosylcobinamide guanylyltransferase where a P-loop is located at the end of the first strand. Strikingly, the nucleotide in the MgATP.CobA complex binds to the P-loop of CobA in the opposite orientation compared to all the other nucleotide hydrolases. That is, the gamma-phosphate binds at the location normally occupied by the alpha-phosphate. The unusual orientation of the nucleotide arises because this enzyme transfers an adenosyl group rather than the gamma-phosphate. In the ternary complex, the binding site for hydroxycobalamin is located in a shallow bowl-shaped depression at the C-terminal end of the beta-sheet of one subunit; however, the active site is capped by the N-terminal helix from the symmetry-related subunit that now extends from Gln(7) to Ala(24). The lower ligand of cobalamin is well-ordered and interacts mostly with the N-terminal helix of the symmetry-related subunit. Interestingly, there are few interactions between the protein and the polar side chains of the corrin ring which accounts for the broad specificity of this enzyme. The corrin ring is oriented such that the cobalt atom is located approximately 6.1 A from C5' of the ribose and is beyond the range of nucleophilic attack. This suggests that a conformational change occurs in the ternary complex when Co(III) is reduced to Co(I).
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PMID:Three-dimensional structure of ATP:corrinoid adenosyltransferase from Salmonella typhimurium in its free state, complexed with MgATP, or complexed with hydroxycobalamin and MgATP. 1114 30

The specific activity and the kinetic properties of partly purified pyruvate kinase (PK) (EC 2.7.1.40) from the Northern Krill, Meganyctiphanes norvegica, were investigated in relation to varying food resources. In order to evaluate the effect of starvation on the total energy metabolism, the respiration rates of fed and unfed krill were determined. The FPLC-elution profile of PK displayed two distinct peaks - PK I and II. The first isoform represented 80% of the total PK activity in the organism, and 20% was contributed by the second isoform. PK I was inhibited by ATP but was not influenced by fructose-1,6-bisphosphate (FBP). In contrast, PK II showed ATP inhibition and up to 2.5-fold increased activity by addition of 17 micromol.l(-1) FBP. The Michaelis-Menten constants of both isoforms were 2-10-fold higher for ADP than for phosphoenolpyruvate (PEP). Alanine showed no regulatory effect on PK I and II. In specimens starved for 7 days oxygen consumption decreased by 20%. Neither the feeding experiments nor the animals captured in the field during low and high productive seasons indicate that PK properties of M. norvegica are modified in relation to food supply. Accordingly, alternative mechanisms are involved in the depression of the metabolic rate in terms of oxygen consumption.
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PMID:Studies on metabolic properties in the Northern Krill, Meganyctiphanes norvegica (Crustacea, euphausiacea): influence of nutrition and season on pyruvate kinase. 1115 47

The feeding of lactating goats on usual green fodder, contaminated with Euphorbia helioscopia or E. nubica, results in poisoning of the dams as well as their suckling kids. General signs of toxicity were emaciation, depression, shedding of body hair, arching of back, and possible death. Post-mortem changes of dams and dead suckling kids included congestion and hemorrhage in cardiac muscle, lung, liver, and kidneys. Blood analyses of goats exposed to these contaminants showed an increased level of serum alanine amino transferase compared to control samples, indicating cellular destruction in the liver. The latter was confirmed by histopathological changes in the organ which include severe congestion, necrosis, and degenerative changes. The goats also suffered from deterioration of renal function as indicated by increased blood urea nitrogen and creatinine levels. In histopathologic inspections of kidney, severe congestion, hemorrhage in the cortex and medulla, as well as necrosis of epithelial cells of kidney tubules were noticed. Considerable degenerative changes were also observed in heart and lung. The pathophysiological appearances indicate that by feeding on the Euphorbia species mentioned above, the goats are poisoned in a way similar to the case of E. peplus reported previously. Such intoxication most likely is due to irritant and hyperplasiogenic diterpene ester (DTE) toxins, usually present in the aerial parts of Euphorbia species and well known as tumor promoters in mouse skin. After ingestion of the toxic plant parts by the goats, the DTE toxins might be metabolized and thereby partially detoxified. Yet, at least in part, they may show up in the milk of the goats, as indicated by severe poisoning of their suckling kids. As discussed previously in lactating goats fed on fodder contaminated with E. peplus, tumor promoters of the DTE type may enter the human food chain via this source of milk. Such milk may be considered a valuable etiologic model for the investigation of economic, ecologic, and public health problems raised by human diet polluted with tumor promoters, i.e., conditional (non-genotoxic) cancerogens.
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PMID:Dietary cancer risk from conditional cancerogens (tumor promoters) in produce of livestock fed on species of spurge (Euphorbiaceae). IV. Toxicologic and pathophysiologic observations in lactating goats and their suckling kids fed on the irritant herbs Euphorbia nubica and Euphorbia helioscopia: an etiologic model for investigations on the putative risk of cancer by consumption of food p. 1120 69

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