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

Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
 ...
PMID:Structure of a cannabinoid receptor and functional expression of the cloned cDNA. 216 65

The participation of the adenylate cyclase system in the short-lived changes in the efficiency of synaptic transmission of a functionally identified synapse of the edible snail has been investigated. It was established that imidazole (a phosphodiesterase activator) in a concentration of 5 mM and tolbutamide (an inhibitor of cAMP-dependent phosphorylation) in a concentration of 2 mM do not alter the rate of the depression of EPSPs which is elicited by rhythmic stimulation at a frequency of 0.1 Hz, and do not block heterosynaptic facilitation. At the same time, both of these substances decrease the amplitude of EPSPs. The possibility of the modulation of the efficiency of synaptic transmission through the adenylate cyclase system is discussed.
 ...
PMID:Role of cyclic adenosine monophosphate in simple forms of plasticity in the edible snail. 217 Aug 58

Cinnamic acid inhibits the O2(-)-generating response of guinea pig peritoneal macrophages elicited with a chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (fMLP), but not those with ovalbumin complex of immunoglobulin G2 antibody and phorbol-myristate acetate. During the course of study on the inhibitory mechanism of cinnamic acid, we found that the acid also inhibited the Ca2+ mobilization elicited with fMLP, but not that with the immune complex. In addition, the treatment of macrophages with Ionomycin and ethyleneglycol bis-(beta-aminoethylether)-N,N'-tetraacetic acid for depletion of the intracellular Ca2+ inactivated completely the O2- generation elicited with fMLP, but not its counterpart of the immune complex. Thus, the inhibitory activity of cinnamic acid on the O2- generation elicited with fMLP seems partly due to that on the Ca2+ mobilization. On the other hand, cinnamic acid augmented the intracellular accumulation of adenosine 3',5'-cyclic monophosphate (cyclic AMP) in the presence of 3-isobutyl 1-methylxanthine (IBMX), and elevated more intensively the concentration of cyclic AMP when macrophages were stimulated with fMLP. Since IBMX inhibited the O2- generation elicited with fMLP, the enhancement of activation of an adenylate cyclase by cinnamic acid might cause depression of the O2- generation. This possibility, however, seems to be excluded by the fact that the same effect of cinnamic acid was observed even when macrophages were stimulated with the immune complex.
 ...
PMID:Different effects of cinnamic acid on the O2- generation by guinea pig macrophages stimulated with a chemotactic peptide and immune complex. 217 2

The effects of a chronic partial depletion of rat cortical NE by a single dose of xylamine (20 mg/kg i.p.) on pre- and postsynaptic noradrenergic functionality were studied 4 hr, 14, 21 and 35 days after treatment. This dose of xylamine resulted in a 40 to 50% selective decrease in cortical levels of NE and the major metabolites of NE, 3,4-dihydroxyphenylethyleneglycol and 3-methoxy-4-hydroxyphenylethyleneglycol and, when measured after 35 days, [3H]desipramine binding and dopamine-beta-hydroxylase activity were at control levels, which would indicate that the NE nerve terminals in the cortex were intact. The 21- or 35-day deficit of NE did not affect alpha-1, alpha-2, beta, dopamine2, 5-hydroxytryptamine, or gamma-aminobutyric acidB receptor densities, or the beta receptor mediated adenylate cyclase activity. In addition, desipramine (10 mg/kg i.p.) administration for 14 days (days 20 through 34) was able to down-regulate beta receptor number (16% decrease) and reduce NE-stimulated adenylate cyclase activity (22% decrease), indicating that postsynaptic plasticity was still maintained. Affective disorders do not appear to be associated with a substantial (or readily measurable) decrease in brain NE concentrations and there is no consistent evidence of an altered beta receptor responsiveness. Thus, partial depletion of NE with xylamine might represent a biochemical model reflecting the involvement of NE in depression which could be used to investigate more sensitive markers of altered noradrenergic function.
 ...
PMID:A low dose of xylamine produces sustained and selective decreases in rat brain norepinephrine without evidence of neuronal degeneration. 245 67

The synthesis of carnosine (beta-Ala-His) by astroglia-rich primary cultures was much higher if the cells were cultivated in Ham's nutrient mixture F-12 than if they were grown in Dulbecco's modified Eagle's medium. Carnosine synthesis was not affected by the presence of insulin, transferrin, phorbol myristate acetate, or dexamethasone. However, dibutyryl cyclic AMP and other agents that can, directly or indirectly, activate cyclic AMP-dependent protein kinases strongly lower the rate of carnosine synthesis. The depression of carnosine synthesis was dependent on the concentration of dibutyryl cyclic AMP. The effect was maximal (approximately 80% inhibition) in cultures preincubated with 1 mM dibutyryl cyclic AMP for 4 days. The adenylate cyclase activator forskolin, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, and 8-bromo-cyclic AMP caused the same depression as dibutyryl cyclic AMP, whereas neither butyrate nor dibutyryl cyclic GMP elicited any effect.
 ...
PMID:Regulation by dibutyryl cyclic AMP of carnosine synthesis in astroglia-rich primary cultures kept in serum-free medium. 246 17

Scattered light intensity fluctuation (SLIF) of coherent light by a strip of ventricular muscle during diastole is believed to be due to asynchronous cellular motion within the myocyte as a result of spontaneous release of Ca from the sacoplamic reticulum. Previous studies have shown a correlation between inotropic agents, such as ouabain and elevated extracellular Ca or decreased extracellular Na, and SLIF. The purpose of this study was to see if this correlation could be extended to other inotropic agents. The digitalis genin, ouabagenin, produces inotropy by increasing intracellular free Ca. In toxic concentrations the drug produces abnormal aftercontractions by spontaneous Ca release from the sarcoplasmic reticulum. On the other hand, the Ca channel agonist BAY k 8644 is also positively inotropic, but its effect is associated with a decrease in Ca release from the sarcoplasmic reticulum, manifested by conversion of "rest potentiation" to "rest depression." The effects of these inotropic agents on the power spectra of SLIF were dissimilar. Both frequency and amplitude of SLIF were increased after ouabagenin (1 microM), but these changes were most marked after the onset of toxicity, at which time contractility was decreased, rather than during the positive inotropic response. In contrast, BAY k 8644 (1 microM) decreased SLIF at all levels of inotropic response. The beta-adrenoceptor stimulant drug, dobutamine, and the adenylate cyclase activator, forskolin, produced minimal increase in SLIF at inotropic concentrations but caused a large increase in SLIF only after the onset of toxicity. These results suggest that SLIF is a better indicator of intracellular Ca overload and toxic oscillatory contractions in the presence of an inotrope and not of increased inotropy, per se.
 ...
PMID:Scattered light intensity fluctuation in the canine ventricular myocardium: correlation with inotropic drug effect. 246 27

1. The mechanism by which acetylcholine (ACh), by stimulation of muscarinic receptors, acts to inhibit activation of the hyperpolarization-activated 'pacemaker' current, if was investigated in isolated rabbit sino-atrial (SA) node myocytes. 2. Intracellular loading with GTP gamma S, a non-hydrolysable analogue of GTP, did not impair the ACh action on if, but made it irreversible. On the other hand, the ACh action on if disappeared after a few minutes of cell loading with GDP beta S, a GDP analogue known to bind to G-proteins and prevent their receptor-stimulated action. Furthermore, incubation of cells in a solution containing pertussis toxin (PTX) led to abolition of the if response to ACh. These results indicate that the inhibitory effect of ACh on if is mediated by G-proteins activated by muscarinic receptors. 3. Intracellular loading with phosphodiesterase (PDE) increased the rate of if current run-down, but did not abolish the inhibitory action of ACh on if. 4. Extracellular perfusion with isobutylmethylxanthine (IBMX), a PDE inhibitor, increased if activation by shifting the current activation range to more positive voltages, as inferred by a three-pulse protocol analysis; in the presence of IBMX, the inhibition of if by ACh was not abolished. 5. The ACh-induced if depression persisted also in cells loaded with cyclic GMP. In these cells, as in those loaded with PDE, the if run-down was fast. 6. Oxotremorine, a muscarinic agonist coupled to adenylate cyclase but not to phosphoinositide turnover in cardiac cells, simulated ACh in its inhibitory action on if. The above results rule against the ACh action being mediated by PDE or by phosphoinositide turnover. 7. To investigate the possible involvement of cyclic AMP as a second messenger in the ACh action on if, we loaded cells with cyclic AMP and IBMX; under these conditions the action of ACh disappeared within a few minutes of whole-cell recording. 8. In cells where the slow inward Ca2+ current (isi) was measured together with if, ACh was seen to depress both currents. 9. In cells superfused with forskolin, the if amplitude on stepping to the half-activation voltage range was enhanced as a consequence of a depolarizing shift of the activation curve; ACh was not effective on if following stimulation by forskolin, but strongly depressed in the same cell the if current stimulated to a similar degree by isoprenaline.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Muscarinic control of the hyperpolarization-activated current (if) in rabbit sino-atrial node myocytes. 247 9

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.
 ...
PMID:Present use of positive inotropic drugs in heart failure. 248 Apr 92

It is suggested that affective disorders arise from the dysbalance of the two major intraneuronal signal amplification systems, the adenylate cyclase and the phospholipase C system, with depression resulting from underfunction of cyclic adenosine 3',5'-monophosphate-mediated effector cell responses associated with an absolute or relative dominance of the inositoltriphosphate/diacylglycerol-mediated responses and mania resulting from the converse. The usefulness of this hypothesis is discussed with respect to (a) the mechanism of action of current therapeutic agents and (b) the development of novel therapeutic approaches.
 ...
PMID:Dysbalance of neuronal second messenger function in the aetiology of affective disorders: a pathophysiological concept hypothesising defects beyond first messenger receptors. 253 71

We have examined the effect on rat liver glucagon receptors and adenylate cyclase activity of a high saturated fat diet (butter fat), a high n-6 polyunsaturated fat diet (corn oil), and a high n-3 polyunsaturated fat diet (menhaden fish oil) with or without additional cholesterol. The number and affinity of the glucagon receptors were unaffected by diet. The glucagon-stimulated adenylate cyclase activity from fish oil-fed animals exhibited the greatest stimulation, followed by corn oil-fed animals. Butter fat-fed and all cholesterol-supplemented groups showed a depression in stimulation. The pattern of adenylate cyclase activity with fluoride stimulation was similar to that observed with glucagon. The effect of dietary fat on forskolin stimulation was similar to glucagon and fluoride for the groups without added cholesterol. However, the cholesterol-supplemented groups did not exhibit a decreased activity. It is suggested that the effect of dietary lipid on glucagon-stimulated adenylate cyclase is not due to changes in the glucagon receptor, but rather due to changes in signal transduction, the Gs-protein or the catalytic unit.
 ...
PMID:Effect of dietary fat and cholesterol supplements on glucagon receptor binding and adenylate cyclase activity of rat liver plasma membrane. 253 45


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>