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 synthesis of at least six enzymes implicated in methionine biosynthesis in Saccharomyces cerevisiae is regulated pleiotropically by two independent regulatory systems. Repression of enzyme synthesis is promoted either by exogenous methonine or by exogenous S-adenosylmethionine (SAM). The regulatory system acting in methionine mediated repression seems to comprise methionyl-tRNA-met as a co-repressor and the other system, acting in SAM repression, comprises SAM as a co-repressor. This concept gives a role in regulation to the two activated forms of methionine. Moreover, evidence is presented that the "SAM repressor" probably acts at a post-transcriptional level while the "met-tRNAmet repressor" would be active at the transcriptional level. These conclusions have been based on two series of experiments: one using a mutant bearing a modified methionyl-tRNA synthetase [L-methionine: tRNA-met ligase (AMP-forming) E.C.6.1.1.10] and one studying the kinetics of depression of synthesis of one of the biosynthetic enzymes after repression either by exogenous methionine or by exogenous SAM. Our results are strengthened by the use of two different drugs: one inhibiting messenger RNA synthesis and the other inhibiting protein synthesis.
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PMID:Regulation of methionine synthesis in Saccharomyces cerevisiae operates through independent signals: methionyl-tRNAmet and S-adenosylmethionine. 78 67

Based on the results of an open trial with Ro 8-1998 (chemic name: N,N-dimethyl-3-(1-methyl-5H-dibenzo(a,d)cycloheptene-5-ylidene)-propylamine N-oxide hydrochloride) in 11 endogenous depressed outpatients a double-blind trial with imipramine was proposed. Therapeutic efficacy and side effects of Ro 8-1998 and imipramine were compared in a double-blind trial with 30 patients who were newly hospitalized. Most of them suffered from endogenous depression. On days 0, 5, 10, 15 and 20 the patients were examined and the symptoms were documented with the AMP system, the Hamilton scale for depression, a behaviour rating and the "global depression rating Zurich". Ro 8-1998 caused a decrease of systolic blood pressure, an increase of heart frequency and urea. Twelve out of 15 patients showed a decrease of white blood cells. In four patients the number of white blood cells dropped below 4,000. Statistical analyses proved both substances to be potent antidepressants. The therapeutic efficacy of Ro 8-1998 was at least equal to that of imipramine. Further trials with bigger groups of patients are necessary to show whether the trend towards a better antidepressant efficacy of Ro 8-1998 can be reproduced.
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PMID:Open trial and double-blind clinical trial of the antidepressant Ro 8-1998 in comparison with imipramine. 87 18

Rats aged 7, 30 days and 3-5 months were given intraperitoneally single doses (2.5 mg/kg) of reserpine. The content of the adenyl system compounds (ATP, ADP, AMP and inorganic phosphorus) was determined. It was shown that as regards the extent of ATP and ADP depression the 7-day old animals proved more sensitive to reserpine than were adult animals.
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PMID:[Age-related characteristics of the reaction of the myocardial adenyl system to pharmacological sympatholysis]. 122 80

The covalent modification of receptor proteins via phosphorylation and dephosphorylation is one of the principal mechanisms controlling carbohydrate metabolism and is known to be regulated by various protein kinases. Recent studies indicated that many hormones may exert their effects on cellular metabolism by regulating intracellular c-AMP levels and by activating a c-AMP dependent protein kinase, i.e., protein kinase A. The metabolic disturbances during sepsis are characterized by an initial hyperglycemia followed by a progressive hypoglycemia and a depletion of hepatic glycogen content. The latter is coupled with a slowdown in glycogenesis, an accelerated glycogenolysis, and a depression in gluconeogenesis in the liver. Since the liver is the major organ that regulates the homeostatic level of blood glucose, it is conceivable that the sepsis-induced glucose dyshomeostasis might be mediated by changes in protein kinase activity and the kinetic characteristics of enzymes. The present experiment was designed to study the correlation between protein kinase A and the pathophysiology of hepatic glucose dyshomeostasis during sepsis. Sepsis was induced in rats by cecal ligation and puncture (CLP). Late sepsis occurred 18 hours after CLP. Protein kinase A was extracted from the rat livers by acid precipitation and ammonium sulfate fractionation, and then partially purified by DEAE-cellulose. The results show that in the late sepsis, type-I protein kinase A (eluted at low ionic strength) activity was significantly decreased by 34-52% (P < 0.01). The kinetic parameters such as Vmax's for ATP, histone, and c-AMP were also significantly decreased from the control values of 6.1 +/- 0.9, 5.4 +/- 0.8, and 5.1 +/- 1.9 nmoles/mg.min. to 3.6 +/- 0.5, 2.8 +/- 0.3, and 2.5 +/- 0.5 nmoles/mg.min., respectively. Analysis using Hill's equation indicates that the S0.5 and n (Hill coefficient) values of the various substrates and activators for type-I protein kinase A remained unchanged. In the case of type-II protein kinase A (eluted at high ionic strength), the Vmax, S0.5, and n values for ATP, histone, and c-AMP were unchanged during late sepsis. The results of the present study indicate that the activities and kinetic characteristics of type I protein kinase A in rat liver are modified during late sepsis. Since protein kinase A is known to regulate glucose metabolism through adrenergic receptor mediation, these findings may have a pathophysiological significance in the understanding of hepatic glucose dyshomeostasis during sepsis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Kinetic studies of protein kinase A in rat liver during late sepsis]. 129 61

The catecholamines, adrenaline and noradrenaline, are released into the circulation of fish during a variety of physical and environmental disturbances that share the common feature of a requirement for enhanced blood oxygen transport. Indeed, the dominant factor controlling the mobilization of catecholamines from chromaffin tissue is a depression of blood oxygen content usually coinciding with a reduction of hemoglobin-O2 (Hb-O2) binding to 50-60% saturation. The elevation of plasma catecholamine levels, under such conditions, activates a beta-adrenergic cyclic AMP-dependent Na+/H+ exchanger on the red blood cell (rbc) membrane. The adrenergic responsiveness AMP-dependent Na+/H+ exchanger on the red blood cell (rbc) membrane. The adrenergic responsiveness of the rbc Na+/H+ exchanger to catecholamines varies both within and between species. Such inter- and intra-specific differences may reflect, in part, the availability of cell surface beta-adrenoceptors that are functionally coupled to adenylate cyclase. The activation of rbc Na+/H+ exchange and the accompanying profound adjustments of intracellular and extracellular acid-base status, nucleoside triphosphate (NTP) levels, and cooperativity of Hb-O2 binding have important consequences on both O2 and CO2 transfer and transport in the blood that vary markedly at the sites of oxygenation (the gill) and deoxygenation (the tissues) thereby enabling simultaneous amelioration of O2 loading and unloading. At the gill, oxygen transfer is enhanced owing to increases in Hb-O2 affinity and capacity while at the tissues, oxygen delivery is facilitated by a reduction of Hb-O2 affinity. This reduction in affinity at the tissues is a consequence of the combined effects of increased cooperativity of Hb-O2 binding and a rise in venous PCO2 (PvCO2) caused by the titration of HCO3- by H+ extruded by the rbc Na+/H+ exchanger. This elevation of PvCO2 may contribute to the rise in arterial PCO2 (PaCO2) observed after adrenergic activation of rbc Na+/H+ exchange that is caused primarily by impairment of rbc CO2 excretion related to modification of the intracellular acid-base status.
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PMID:Control and consequences of adrenergic activation of red blood cell Na+/H+ exchange on blood oxygen and carbon dioxide transport in fish. 132 42

1. The catecholamine-induced Cl- current and the Ca2+ current were recorded in the single ventricular cells of guinea-pig hearts, using the whole-cell patch clamp technique combined with internal perfusion. Dependence of the beta-adrenergic responses on external monovalent cations was investigated. The Cl- current was recognized by measuring the reversal potential of the agonist-induced current. 2. The amplitude of the Cl- current, activated by 1 microM adrenaline or 0.01-0.1 microM isoprenaline, was decreased when the external Na+ concentration ([Na+]o) was reduced by replacement with Tris+. The conductance of the catecholamine-induced Cl- current was proportional to the logarithm of the [Na+]o over a range of 15-140 mM. When the conductance was plotted against the concentration of Tris+, a dose-dependent inhibition of the Cl- response by Tris+ was suggested with a half-maximum concentration of 95 mM. 3. The inhibitory effect of the Na+ substitute TEA+ on the Cl- current was not affected by either increasing the buffer for the internal Ca2+ (10 mM BAPTA) or for the pH (50 mM HEPES). 4. In the relationship between agonist concentration and the Cl- conductance, the half-maximum concentration (K1/2) of isoprenaline was 0.013 microM in the control Na+ solution, and was shifted to 0.07, 0.08, 0.1 and 0.3 microM in the Li+, Cs+, TEA+ and Tris+ external solutions, respectively. The maximum slope conductance was not significantly affected, except for a slight depression on the Tris+ solution. When the current was induced by adrenaline, qualitatively the same finding was obtained; K1/2 was 0.15 and 3.2 microM in the Na+ and Tris+ solutions, respectively. 5. As a substitute for the external Na+, sucrose seemed to be inert. The activation of the inward Cl- current was conserved in the 300 mM sucrose solution ([Cl-]o = 8 mM) with a K1/2 value of 0.015 microM isoprenaline. 6. The Cl- current, when activated by either an external application of forskolin (0.2-10 microM) or an internal perfusion of cyclic AMP (100-500 microM), was not affected by replacing external Na+ with other cations. Activation of the Cl- current by 0.2-5 microM histamine was also insensitive to a substitution of Na+. These findings indicate that the inhibition by the Na+ substitute is at a point before the activation of GTP-binding protein. 7. The effects of Na+ substitution were not affected by varying the Na+ concentration (0-115 mM) in the internal solution, excluding an involvement of a change in the [Na+]i.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of beta-adrenergic responses of chloride and calcium currents by external cations in guinea-pig ventricular cells. 133 57

Regulation of catecholamine biosynthesis is crucial in the adaptation to various physiological conditions, such as stress, and in several disorders, including hypertension and depression. In this study we have found that in PC12 cells, the mRNA levels of dopamine beta-hydroxylase (DBH), the enzyme that catalyzes the formation of norepinephrine from dopamine, can be regulated by glucocorticoids and cyclic AMP (cAMP) analogues. Treatment with dexamethasone increased DBH mRNA levels by 6 h. with maximal elevation (four- to fivefold) obtained after 1 day of exposure, and these levels were maintained for up to 4 days. DBH mRNA levels were also elevated on treatment of PC12 cells with 8-bromo cAMP for 8 h to 1 day. The response to 8-bromo cAMP, however, was bimodal, because DBH mRNA levels declined below control values on treatment for > 1 day. In combined treatments with 8-bromo cAMP and dexamethasone, the cAMP effect was dominant. To begin to characterize the regulation of DBH mRNA, genomic clones for rat DBH were isolated, and 1 kb of the 5' flanking region was sequenced. Several putative regulatory elements, which may be involved in cAMP and glucocorticoid regulation, were identified, including two adjacent cAMP response elements, another element that can also bind members of the ATF/CREB family of transcription factors, a NF-kappa B-like sequence, several AP-2 sites, and three core glucocorticoid receptor binding sequences.
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PMID:Regulation of expression of dopamine beta-hydroxylase in PC12 cells by glucocorticoids and cyclic AMP analogues. 135 11

1. Basal release of endothelium-derived relaxing factor (EDRF) rendered endothelium-containing rings of rat aorta 4.7 fold less sensitive to the contractile actions of phenylephrine and depressed the maximum response when compared with endothelium-denuded rings. The responsiveness and maximum response to phenylephrine was, however, similar in rings of rabbit aorta with or without endothelium. 2. Rotenone (1 nM-0.1 microM), an inhibitor of oxidative phosphorylation, induced a profound, irreversible blockade of phenylephrine-induced tone in endothelium-containing and endothelium-denuded rings of rat aorta, but induced only slight inhibition of tone in rings of rabbit aorta. 3. 2-Deoxy glucose (10 mM), an inhibitor of glycolysis, had no effect on phenylephrine-induced contraction in endothelium-denuded rings of rat aorta, but inhibited reversibly the endothelium-dependent depression of contraction in endothelium containing rings. 2-Deoxy glucose had no effect on phenylephrine-induced contraction in rings of rabbit aorta with or without endothelium. 4. Rotenone (0.1 microM) inhibited acetylcholine-induced, endothelium-dependent relaxation of phenylephrine-contracted rings or rat and rabbit aorta. In endothelium-denuded rings of rat aorta, relaxation induced by glyceryl trinitrate of isoprenaline was also inhibited, but relaxation induced by 8-bromo cyclic GMP or dibutyryl cyclic AMP was not. Relaxation induced by verapamil on KCl-contracted, endothelium-denuded rings of rat aorta was also unaffected. 5. 2-Deoxy glucose (10 mM) inhibited acetylcholine-induced, endothelium-dependent relaxation of phenylephrine-contracted rings of rat and rabbit aorta. In endothelium-denuded rings of rat aorta, relaxation induced by glyceryl trinitrate and by isoprenaline was also inhibited, but relaxation induced by 8-bromo cyclic GMP or dibutyryl cyclic AMP was not. Relaxation induced by verapamil on KCIcontracted, endothelium-denuded rings of rat aorta was also unaffected. 6. These data suggest that in rabbit and in rat aorta, rotenone inhibits acetylcholine-induced relaxation by inhibiting EDRF production, and by depressing smooth muscle sensitivity to EDRF, respectively. They further suggest that 2-deoxy glucose inhibits acetylcholine-induced relaxation in both tissues by depressing the sensitivity to EDRF, probably as a result of reduced synthesis of cyclic GMP. The additional possibility that 2-deoxy glucose inhibits EDRF production warrants further investigation. 7. The blockade by 2-deoxy glucose of the endothelium-dependent depression of phenylephrine-induced tone in rat aorta probably reflects blockade of the actions of spontaneously released EDRF.
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PMID:Effects of metabolic inhibitors on endothelium-dependent and endothelium-independent vasodilatation of rat and rabbit aorta. 164 55

Hormonal modulation of neurotransmission emerged as a concept from the recognition that adrenocortical steroids exert profound effects at the level of receptors, G-proteins and effector units. G-proteins, a family of guanine nucleotide binding regulatory components that couple neurotransmitter receptors to various types of intracellular effector systems, appear to be a key target of glucocorticoid (GC) action in the CNS. It is thought that Gs/Gi mediates stimulation/inhibition of adenylate cyclase (AC system), which forms cyclic AMP as second messenger, while receptors stimulating phospholipase C do so through Go to produce two second messengers, inositol 1,4,5-triphosphate and diacylglycerol (PI system). Recent evidence suggests that GC increase Gs alpha-and decrease Gi alpha-protein subunit expression without affecting Go alpha. Activation of central pre- and postsynaptic 5-HT1A receptors which are linked to the Gi-AC complex, induces hypothermia and ACTH/cortisol release in rodents and humans. Compared with controls, patients with a major depressive disorder exhibit increased basal cortisol secretion associated with decreased hypothermic and ACTH/cortisol responses. The attenuated neuroendocrine and thermoregulatory response to 5-HT1A receptor activation may reflect a GC-dependent feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) system and subsensitivity of the presynaptic 5-HT1A-Gi-AC complex function. Differential regulation of 5-HT1A and 5-HT2 function leading to a relative 5-HT2-Go-PI complex supersensitivity may maintain HPA hyperactivity during the course of depression. These findings corroborate recent reports that GC, via GC-GC receptor (GR) complex activated promotion of gene transcription, modify the expression 5-HT1A-coupled Gi (but not 5-HT2-coupled Go) resulting in altered sensitivity of 5-HT1A-mediated signal transduction and further support the hypothesis of a differential regulation of 5-HT1A and 5-HT2 receptor function and a GC-GR/5-HT1A-G-protein--effector system-related abnormality in depression.
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PMID:The 5-HT receptor--G-protein--effector system complex in depression. I. Effect of glucocorticoids. 164 69

1. After blocking K+ currents with 10 mM-tetraethylammonium (TEA) or TEA plus 250 microM-3,4-diaminopyridine (3,4-DAP). motor nerve terminal Ca2+ currents were recorded using focal extracellular electrodes. Two transmitters released from the terminal. ATP and acetylcholine (ACh), were then applied, and the effects on the nerve terminal Ca2+ current were measured. 2. ATP (50 microM) reduced the Ca2+ current by 34%, but this action is prevented when hydrolysis to adenosine is blocked by alpha,beta-methyladenosine 5'-diphosphate (200 microM). Thus, inhibition by ATP presumably occurs subsequent to ATP hydrolysis to adenosine. 3. Adenosine (50 microM) inhibited the terminal Ca2+ current by 29%. This was mimicked by the adenosine analogue L-phenylisopropyl adenosine (L-PIA) and blocked by theophylline (100 microM), which antagonizes adenosine receptors at micromolar concentrations. 4. ACh (100 microM) or the anticholinesterase methane sulphonyl fluoride (MSF; 1 mM) also depressed the terminal Ca2+ current. This response was mimicked by muscarine (100 microM) and antagonized by atropine (100 microM) or pirenzipine (4 microM), which is generally specific for M1 receptors. 5. Addition of Ba2+, which blocks adenosine-mediated K+ currents, had no effect on the inhibitory effects of either adenosine or ACh; similarly, neither adenosine nor ACh in the bath affected K+ current records obtained after blocking all inward currents with 10 mM-Co2+ and focal application of tetrodotoxin. 6. Incubation of the muscle for 4 h in pertussis toxin (10(-5) g ml-1) eliminated both adenosine- and ACh-induced inhibition of the terminal Ca2+ current. This result indicates the possible involvement of a G protein in the transduction of the feedback pathway. 7. Neither cyclic AMP analogues, the adenylate cyclase activator forskolin (10 microM), the phorbol ester phorbol 12-myristate 13-acetate (PMA; 3 microM) nor the diacylglycerol analogue 1,2-oleoylacetylglycerol (OAG; 3 microM) had any effect on adenosine- or ACh-induced depression of the terminal Ca2+ current. Therefore, pathways involving these particular second messengers are most probably not involved. 8. The effects of adenosine and ACh are non-additive. 9. These results indicate that ATP and ACh, which are released during exocytosis, may inhibit their own release through attenuation of the terminal Ca2+ current via autoreceptors coupled to a G protein.
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PMID:Autoreceptor-mediated purinergic and cholinergic inhibition of motor nerve terminal calcium currents in the rat. 165 22


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