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)

Previous work demonstrated that parathyroid hormone (PTH) activates the Ca2+/protein kinase C (PKC) system in addition to cAMP production. Therefore, the authors explored the role of cAMP-dependent and Ca2(+)-dependent signals in the regulation of osteoblastic growth and bone resorption. In exponentially growing UMR 106-01 osteogenic sarcoma cells, PTH (10(-7) M) inhibited [3H] thymidine incorporation by 80%. This effect was reproduced by maximal doses of both dibutyryl-cAMP (dbcAMP) and forskolin. The Ca2+ ionophore ionomycin (10(-7) M) had no effect, whereas phorbol 12-myristate 13-acetate (PMA) was slightly mitogenic. The antimitogenic action of dbcAMP was dose-dependent, with ED0.5 at about 3 X 10(-5) M. Ionomycin enhanced this dbcAMP effect at submaximal doses of the cAMP analog. PMA used in combination with both dbcAMP and ionomycin induced further depression of cell proliferation, indicating synergism with cAMP. Both dbcAMP (10(-4) M) and ionomycin (10(-7) M) stimulated 45Ca release from fetal rat limb bones after five days in culture, although the Ca2+ ionophore was less potent. 1-Oleoyl 2-acetyl-glycerol (2 X 10(-6) M) was ineffective alone, and slightly inhibited the 45Ca release produced by the other second messenger analogs in all combinations. The combination of dbcAMP and ionomycin showed a synergistic effect, and fully reproduced PTH effect. In conclusion, PTH signal transduction for control of cell proliferation and bone resorption is mediated mainly by cAMP. Activation of the Ca2+/PKC message system is nevertheless necessary to express a full hormonal response in both cell and organ culture systems.
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PMID:Cyclic AMP-dependent and calcium-dependent signals in parathyroid hormone function. 217 68

Rapid and prolonged effects of recombinant human interleukin-1 alpha (IL-1 alpha) on mouse thyroid were studied. After daily administration of 15 micrograms or 1 microgram IL-1 for 7 consecutive days, serum T4 concentrations rapidly fell to undetectable levels but returned to near control level after the cessation of IL-1. On the 31st day, 3 weeks after the drug cessation, a significant depression of serum T4 was observed again. In addition, the IL-1-treated mouse thyroid showed an in vitro unresponsiveness to TSH, with an increase of pituitary TSH (2.24-fold by 15 micrograms IL-1). To understand underlying mechanisms further, serial observations were performed. Thyroidal T4 contents increased initially, decreased to a low level at day 14, and returned to approximately the control level. IL-1 administration induced an increase in the basal thyroidal cAMP level for a prolonged period. Its response to TSH showed a gradual decline to a level approximately 30% of the control by the 31st day. Pituitary TSH contents on the 22nd and 31st days showed significant elevations. Slight decreases in thyroidal TSH binding and T4 contents also were seen concomitantly. These studies indicate that an administration of a large dose of IL-1 results in a dramatic decrease in serum T4 primarily through the inhibition of T4 release from the thyroid. The results also indicate the induction of a prolonged hypothyroid state due to the unresponsiveness to TSH via a postreceptor mechanism.
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PMID:Prolonged effects of recombinant human interleukin-1 alpha on mouse thyroid function. 222 18

A complementary DNA (cDNA) clone (B4) encoding the catalytic subunit of a cAMP-dependent protein kinase (PKAc) was isolated from a lambda gt10 rat brain cDNA library, using a synthetic oligonucleotide probe whose sequence was based on the known amino acid sequence of a bovine cardiac PKAc. Sequence analysis of this clone revealed a region of 1002 nucleotides which encodes a protein that is 92% homologous to amino acids 17-350 of the bovine cardiac PKAc protein. This clone lacks coding sequences for amino acids 1-16 of the latter protein. Nevertheless, it provided a useful probe to analyze expression of the related gene in a variety of systems. Northern blot analyses using a 32P-labeled probe prepared from a 0.6-kilobase PstI fragment of clone B4 revealed an abundant 4.6-kilobase band in rat brain RNA and lesser amounts of this 4.6-kilobase RNA in rat heart and liver. A 4.6-kilobase RNA was also detected in RNA samples obtained from mouse fibroblasts. This probe also detected homologous RNA in a variety of nonrodent species. In subsequent experiments, this cDNA was used as a probe to elucidate the role of PKAc in post-surgical hepatic regeneration and diethylnitrosamine-induced hepatomas in the rat. These experiments revealed that, following partial hepatectomy, PKAc mRNA is decreased 3-fold by 12 h, returning to normal by 72 h; hepatomas showed no consistent pattern of change in PKAc mRNA levels as compared to controls. Our results indicate that this cDNA encodes an isoform of PKAc which is distinct from PKAc-alpha isolated by Uhler et al. (Proc. Natl. Acad. Sci. USA, 83: 1300-1304, 1986) but highly homologous to PKAc-beta isolated by Showers and Maurer (J. Biol. Chem., 261: 16288-16291, 1986), that depression of cAMP-dependent protein phosphorylation may be an important mechanism in the regeneration of mature rat liver but is not a consistent alteration in chemically induced hepatoma, and that this cDNA is useful as a probe for the study of the role of PKAc gene expression in growth control, particularly in rodent species.
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PMID:Isolation of a complementary DNA encoding the catalytic subunit of protein kinase A and studies on the expression of this sequence in rat hepatomas and regenerating liver. 230 20

Serotonin (5-HT) has previously been shown to evoke an increase in the duration of the Ca2+-dependent spike of molluscan neurons by decreasing the S current (Klein et al., 1982), a K+ current controlled by cAMP. However, in a group of identified ventral neurons of the snail Helix aspersa in which 5-HT (1-10 microM) also prolonged the duration of the Ca2+-dependent action potential, no 5-HT-induced depression of S current or of any other outward current was observed. Instead, 5-HT was found to evoke the prolongation of the somatic spike by inducing an increase in Ca2+ membrane conductance. This 5-HT-induced increase of Ca2+-current was mimicked neither by the intracellular injection of cAMP nor by the extracellular application of forskolin (20 microM). In contrast, it was mimicked by the intracellular injection of cGMP and by the extracellular application of 100 nM zaprinast, a cGMP-phosphodiesterase inhibitor. The extracellular application of phorbol ester TPA (100 nM), an activator of protein kinase C, was also found to increase the Ca2+ current in the identified snail ventral neurons, but this enhancing effect had a different time course from that induced by 5-HT. These results indicate that there is a second mechanism for prolonging the Ca2+ spike of molluscan neurons, consisting of an increase in Ca2+ current, in which cGMP may play a role as second messenger.
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PMID:Serotonin and cyclic GMP both induce an increase of the calcium current in the same identified molluscan neurons. 242 71

The role of second messenger calcium in cAMP-mediated exocytosis from parotid cell aggregates has been assessed following extracellular (ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA] and intracellular (quin2) calcium chelation. Only in the former case was inhibition (60-70%) of isoproterenol- and N6,O2-dibutyryl cAMP-stimulated amylase release observed. This inhibition was accompanied by a 70% decrease in cellular ATP levels. Depression of ATP levels with mitochondrial inhibitors was also correlated with inhibition of amylase secretion. Overall, our results suggest that depletion of cellular Ca2+ with EGTA leads to an inhibition of mitochondrial function and that these experimental conditions are therefore inappropriate for the evaluation of the role of cytosolic Ca2+ transients during stimulus-secretion coupling.
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PMID:The inhibition of cyclic AMP-mediated exocytosis from rat parotid cells by calcium chelation is due to depression of cellular ATP. 246 Dec 28

cAMP-dependence of synaptic depression and facilitation was investigated in functionally identified synaptic connection in the snail. It was found that 5 mM imidazole (phosphodiesterase activator) as well as 2 mM tolbutamide (inhibitor of cAMP-dependent protein kinase) do not change the rate of EPSPs depression during rhythmic (0.1 Hz) nerve stimulation, and do not affect facilitation. But treatment with both these drugs decreases EPSPs amplitude. Possibility of cAMP-dependent modulation of synaptic effectiveness is discussed.
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PMID:[The role of cyclic adenosine monophosphate in simple forms of plasticity in the edible snail]. 247 62

Cardiac failure is treated with increasing success by phosphodiesterase-III (PDE-III) inhibitors such as amrinone, milrinone, and enoximone. While relatively pure positive inotropic substances (e.g., dopamine and dobutamine) are limited by tolerance development and MVO2 increase, the efficacy of PDE inhibitors is maintained by avoiding catecholamine and beta-receptors. They have positive inotropic, positive lusitropic, and vasodilatatory properties; myocardial oxygen consumption remains unaltered. PDE-III inhibitors act by selectively inhibiting PDE-III, leading to an increased cAMP concentration in myocardial and smooth muscle cells. In contrast, forskolin increases intracellular cAMP by activation of adenylate cyclase. It could be shown that parenteral administration of the PDE inhibitors sulmazole, amrinone, and enoximone resulted in preload and afterload reduction due to vasodilation with concomitant decrease of peripheral and pulmonary vascular resistance; they also led to elevated cardiac output and ejection fraction as well as a significant increase in dp/dtmax, while left ventricular filling pressures were markedly lowered. Pulmonary pressure values fell significantly, whereas heart rate and myocardial oxygen consumption showed no clinically relevant alterations. In patients with angiographically documented coronary artery disease, the anti-ischemic efficacy of enoximone could be proven both during exercise and stress pacing. The decrease of the pathologically elevated pulmonary pressures during ischemia was accompanied by reduced ST-segment depression following enoximone without changing MVO2 significantly. First tests after intracoronary application of enoximone confirmed its direct myocardial efficacy, indicating its positive inotropic and lusitropic properties. Thus, patients in cardiac failure have useful therapeutic alternatives at their disposal when taking PDE inhibitors. The anti-ischemic properties of these drugs need further evaluation.
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PMID:Present use of positive inotropic drugs in heart failure. 248 Apr 92

The present experiments examined the effects of progesterone on adrenergic receptor coupling to adenylate cyclase in hypothalamic and preoptic area slices by monitoring norepinephrine (NE)-stimulated increases in cAMP accumulation. Progesterone treatment of estrogen-primed rats decreased NE-induced slice cAMP accumulation. The reduced cAMP response was estrogen-dependent since it was not demonstrable in slices from rats exposed to progesterone without prior estrogen priming. Neither generalized increases in phosphodiesterase activity nor decreases in the catalytic activity of adenylate cyclase could account for the reduced ability of NE to stimulate cAMP accumulation in hypothalamic slices. Moreover, the cAMP response to two other activators of adenylate cyclase, adenosine and vasoactive intestinal peptide, was not decreased in slices from rats treated with estrogen plus progesterone. Selective adrenergic agonists and antagonists were employed to determine which adrenergic receptors mediate cAMP accumulation in progesterone-exposed slices. Slice cAMP levels were elevated by the beta receptor agonist isoproterenol but not by alpha 1 (phenylephrine) or alpha 2 (clonidine) agonists. However, clonidine potentiated the effect of isoproterenol on slice cAMP formation whereas phenylephrine did not. Likewise, NE-stimulated cAMP accumulation was completely antagonized only by a combination of both beta (propranolol) and alpha 2 (yohimbine) antagonists. The data suggest that in slices from estrogen plus progesterone-treated rats, alpha 2 receptors contribute significantly to NE stimulation of cAMP accumulation. The overall depression of the cAMP response to NE in progesterone-exposed slices may involve a decrease of alpha 1 receptor facilitation of cAMP synthesis.
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PMID:Progesterone depression of norepinephrine-stimulated cAMP accumulation in hypothalamic slices. 254 2

1. Local application of 5-hydroxytryptamine (5-HT) in the area in which a dense 5-HT plexus is located in the lamprey spinal cord leads to a marked depression of the late phase of the afterhyperpolarization (AHP) following the action potential. This effect was observed in motoneurons, premotor interneurons, and giant interneurons, whereas no effect was observed in the sensory dorsal cells and edge cells. 2. The late 5-HT sensitive phase of the AHP was increased in amplitude when calcium entry was enhanced during the prolongation of action potentials caused by tetraethylammonium (TEA). Conversely, a blockade of Ca2+ entry by manganese reduced the AHP amplitude, suggesting that a calcium-dependent current, most likely carried by potassium, underlies the late phase of the AHP in these cells, as is the case in many other types of neurons. 3. The late phase of the AHP could be depressed by 5-HT although no effects were exerted on either the resting input resistance or on the shape of the action potential in 54% of the cells. The membrane conductance increase associated with the late phase of the AHP was markedly attenuated by 5-HT application. 4. In voltage-clamp experiments, Na+ currents and most K+ currents were blocked by tetrodotoxin (TTX) and TEA, respectively. Under these conditions, voltage steps elicited a slow outward current, most likely representing a Ca2+-activated K+ current, which was depressed by 5-HT application. 5. 5-HT does not appear to reduce AHP amplitude by blocking the calcium entry occurring during the action potential. No evidence was obtained for an involvement of second messengers such as adenosine-3':5'-cyclic monophosphate (cAMP), guanosine-3':5'-cyclic monophosphate (cGMP), diacyglycerol, or arachidonic acid. The effect of 5-HT on the late AHP may be due to a direct action on the calcium-dependent potassium channels or on the intracellular handling of Ca2+ ions. 6. The amplitude reduction of the AHP has a profound influence on the spike frequency regulation of any given cell; the frequency of spikes evoked by a given excitatory stimulus is therefore markedly increased by application of 5-HT. 5-HT thus increases the "gain" of the input-output relation of interneurons and motoneurons responsible for generating the locomotor rhythm. In addition, 5-HT causes a prolongation of the depolarized plateau of the N-methyl-D-aspartate (NMDA) receptor-induced membrane potential oscillations, as expected from the 5-HT-induced effects on the Ca2+-activated K+ channels that contribute to the repolarization.
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PMID:Effects of 5-hydroxytryptamine on the afterhyperpolarization, spike frequency regulation, and oscillatory membrane properties in lamprey spinal cord neurons. 254 72

Rabbit reticulocytes were separated into four fractions of different maturity in order to investigate the changes of cellular respiration and glycolysis, adenine nucleotides, 2,3-biphosphoglycerate (2,3-BPG) as well as cyclic AMP level during the transition from the youngest to the most mature reticulocytes. A significant reduction of total oxygen consumption, mainly due to depression of coupled respiration was found. The decline of respiration was accompanied by a 2-fold increase of the rate of aerobic glycolysis indicating a reduced Pasteur effect during maturation. A decline of ATP and an increase of ADP concentration was found. The oxygen-delivery capacity of the red cells increased by about 26% caused by an increase of the 2,3-BPG level of about 2 mmol/l cells. Cyclic AMP level in the fraction of youngest reticulocytes was about 60-fold higher than that in mature rabbit erythrocytes. The biggest decline of cyclic AMP was registered during the transition from youngest to the intermediate stage of maturity.
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PMID:Maturation-dependent changes of the rabbit reticulocyte energy metabolism. 254 58


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