Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ADP-induced platelet aggregation and shape change were monitored optically in citrated rabbit platelet-rich plasma (PRP) diluted with isotonic salt solutions. Lithium (Li) produced a concentration-dependent reduction in the rate of platelet aggregation but had no discernible effect on the shape change which precedes aggregation. When PRP was pre-incubated with Li, the inhibitory effect of the ion was independent of the duration and temperature of the treatment. The inhibitory effect of Li also was observed in heparinized PRP or when 5-HT was used as the aggregation-inducing agent. When Li was combined with aggregation inhibitors which enhance platelet cyclic AMP content either by activating adenylate cyclase or by inhibiting phosphodiesterase, only additive effects were observed. The inhibitory effect of Li was opposed by added calcium. Kinetic evaluation of the interaction between Li and Ca indicated that their antagonism was competitive. Added calcium also displayed competitive antagonism toward the aggregation inhibiting effect of increased hydrogen ion concentration in the pH range between 6 and 8.
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PMID:Competitive inhibition by lithium and hydrogen ions of the effect of calcium on the aggregation of rabbit platelets. 1 92

Rats were subjected to chronic treatment with lithium chloride (0.2-0.3%) over a period of 3 weeks. The activity of cortical phosphodiesterase (EC 3.1.4.17) was determined simultaneously with cyclic AMP and cyclic GMP content and compared to control, untreated animals. Lithium, at therapeutic serum concentrations was found to suppress cyclic AMP levels with a concomitant increase in cyclic AMP-phosphodiesterase activity. A simultaneous two-fold increase in cyclic GMP was observed. Through the alteration of cortical cholinergic activity with physostigmine and the use of cyclic GMP as a cholinergic marker, we were able to demonstrate a novel cholinotropic property of lithium to stimulate synthesis of cyclic GMP. This effect appears to be linked, in a Yin-Yang mechanism, to the observed suppression of cyclic AMP induced by lithium through activation of cyclic AMP-phosphodiesterase.
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PMID:Lithium modulation of cortical cyclic nucleotides: evidence for the Yin-Yang hypothesis. 215 92

Evidence is presented for a novel proposal for the mechanism of action of lithium in manic depressive psychosis. Lithium has well established effects on catecholaminergic--and hormone--stimulated adenyl cyclase activity and on cyclic AMP formation. Although there is conflicting evidence in the literature concerning the effects of the ion on cyclic nucleotide phosphodiesterase, not much is known of the effects of lithium on cyclic GMP. These two second messengers have been proposed to be mutually antagonistic in their actions but that a physiological balance between the two is essential for maintaining homeostasis of the human psyche. An in vivo animal study was undertaken to determine the effects of chronic lithium treatment on the dynamics and kinetics of these two cyclic nucleotides and phosphodiesterase in rat cerebral cortex. From these results, a possible functional coupling mechanism between the two second messenger systems and the effects of lithium are proposed. Lithium by means of its specific site of action, is unique among psychoactive drugs in that it can control both phases of bipolar illness. This point of action is proposed to be the metabolism of free fatty acids where lithium, by altering the availability of precursors for eicosanoid metabolism, is able to modulate both noradrenergic- and cholinergic-dependent pathways. By doing this, the ion is able to reestablish lost control over adrenergic and cholinergic balance critical for thought process and mood stability.
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PMID:A novel hypothesis for the psycho-modulating effects of lithium: the role of essential fatty acids, eicosanoids and sub-cellular second messengers. 219 69

Rolipram is a racemic drug that increases brain cAMP availability by inhibiting phosphodiesterase. Lithium, on the other hand, reduces cAMP levels in brain by inhibiting adenylate cyclase and by increasing phosphodiesterase activity. Inbred strains of mice were used in the present study to determine whether the opposite effects of lithium and rolipram on cAMP levels were evident from behavioural effects of the drugs. In the first experiment, locomotor activity was measured in strains of male and female mice given an injection of either vehicle, (+)- or (-)-rolipram in order to find appropriate test conditions for studying interactions with lithium. (-)-Rolipram was more potent than its antipode in inducing hypokinesia, and the effects of (+)- and (-)-rolipram depended on mouse strain. In the second experiment, mice received lithium in their food for 3-4 weeks prior to testing, and they were then given an injection of vehicle, (+)- or (-)-rolipram before behaviour tests. Lithium reduced locomotor activity in mice given the vehicle, whereas it counteracted activity-suppressant effects of rolipram. The behavioural findings are consistent with the opposite pharmacological effects of lithium and rolipram on cAMP, and support the notion that cAMP availability in brain may play a role in behavioural effects of lithium and rolipram.
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PMID:Effects of lithium and rolipram enantiomers on locomotor activity in inbred mice. 231 65

Lithium (Li) has been reported to inhibit numerous adenylate cyclases, but often these reports used clinically toxic concentrations of Li and their relevance to a theory of Li action was questionable. The present report demonstrated Li inhibition beginning at 2 mM of the norepinephrine (NE)-induced cyclic AMP accumulation in a resuspended P2 pellet containing intact synaptosomes and in slices from rat cortex. The inhibition is demonstrable with isoproterenol as well and in the presence of a phosphodiesterase inhibitor. In cortical slices removed from rats treated for 21 days with therapeutically equivalent Li serum levels, NE-induced cyclic AMP accumulation is inhibited by over 70%. After cessation of 21 or 42 days of Li treatment, an enhancement of cyclic AMP accumulation to NE is not demonstrable. Rubidium and cesium do not inhibit NE-induced cyclic AMP accumulation. These ions cause an increase in basal cyclic AMP accumulation in the absence of NE, as does Li to a lesser degree. The effect of Li to inhibit NE-induced cyclic AMP accumulation is therefore specific to the Li ion, occurs at therapeutically equivalent concentrations, continues after chronic treatment and does not cause a compensatory supersensivity in the manner of the NE-receptor blocking drugs.
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PMID:The effect of lithium on noradrenaline-induced cyclic AMP accumulation in rat brain: inhibition after chronic treatment and absence of supersensitivity. 624 92

The adaptability of the cyclic AMP phosphodiesterase (PDE) following chronic treatment (4-6 weeks) with lithium, reserpine, imipramine, and combinations of lithium with imipramine or reserpine has been studied in rat brain tissue. All drugs, except lithium, were given intraperitoneally once a day. Control animals received only vehicle. Lithium was given in the diet in a concentration yielding a plasma level of 0.5-0.6 mmol/l. The PDE activity was measured in homogenates from cerebral cortex and "limbic" forebrain. These two brain areas were both found to contain three types of PDE activity. One was mainly associated with the pellet after a 10,000 X g centrifugation for 10 min. This enzyme hydrolyzed both cyclic AMP and cyclic GMP with a Km value of 130 +/- 48 microM for cyclic AMP, but was insensitive to calcium and calmodulin. Two types were mainly found in the supernatant after the centrifugation with Km values cyclic AMP of 300 +/- 108 microM and 4 +/- 3 microM, respectively. The former hydrolyzed both cyclic AMP and cyclic GMP and was stimulated 7-fold by calcium and calmodulin, while the latter only hydrolyzed cyclic AMP and was insensitive to calcium and calmodulin. None of the treatments affected the "pellet" enzyme or the low affinity enzyme from the supernatant. However, lithium treatment, even combined with reserpine or imipramine, increased the high affinity enzyme. This increase was also apparent in the DEAE-ion exchange chromatographic profile of the PDE enzymes.
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PMID:Cyclic AMP phosphodiesterase activity in rat brain following chronic treatment with lithium, imipramine, reserpine, and combinations of lithium with imipramine or reserpine. 631 25

Addition of vasopressin to rat hepatocytes prelabeled with myo-[2-3H]inositol resulted in a very rapid decrease [3H]phosphatidylinositol 4,5-bisphosphate (Ptd-Ins-4,5-P2) which was paralleled by increases of up to 3-fold in the levels of [3H]inositol trisphosphate (Ins-P3) and [3H]inositol bisphosphate (Ins-P2). Increases of [3H]inositol phosphate (Ins-P) were not detected until about 5 min after hormone addition. These data indicate that the major pathway for hormone-induced lipid breakdown in liver is through a phosphodiesterase for PtdIns-4,5-P2 and that decreases of phosphatidylinositol are a secondary result of increased PtdIns-4,5-P2 resynthesis. Using the fluorescent Ca2+ indicator Quin 2, cytosolic free Ca2+ increased from 160 nM to about 400 nM after vasopressin addition to hepatocytes and preceded the conversion of phosphorylase b to a. Half-maximal and maximal increases of cytosolic free Ca2+ and phosphorylase a activity were observed at 0.2 and 1 nM vasopressin, respectively. The dose-response curve for the initial rate of cytosolic free Ca2+ increase was very similar to those obtained for the initial rates of Ins-P3 production and PtdIns-4,5-P2 breakdown. Pretreatment of hepatocytes with Li+ caused a 3--4-fold potentiation of vasopressin-induced elevations of Ins-P, Ins-P2, and Ins-P3, with half-maximal effects at 0.5, 1, and 5 mM, respectively. The calculated maximal concentrations of Ins-P3 in cells treated with 20 nM vasopressin were 10 and 30 microM, respectively, without and with Li+. Lithium did not affect the initial rate of inositol polyphosphate production or Ca2+ mobilization. The increase of Ins-P3 which correlated with peak cytosolic free Ca2+ elevation was about 0.6 microM. In a saponin-permeabilized hepatocyte preparation, Ins-P3 (1 microM) caused Ca2+ release from a vesicular, ATP-dependent Ca2+ pool. The data presented here suggest that Ins-P3 may be a second messenger for the mobilization of intracellular Ca2+ by hormones in liver.
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PMID:Relationship between inositol polyphosphate production and the increase of cytosolic free Ca2+ induced by vasopressin in isolated hepatocytes. 632 42

Lithium, a common drug for the treatment of bipolar disorder (BD), requires chronic administration to prevent recurrences of the illness. The necessity for long-term treatment suggests that changes in genes expression are involved in the mechanism of its action. We studied effects of lithium on gene expression in lymphoblasts from BD patients, all excellent responders to lithium prophylaxis. Gene expression was analyzed using cDNA arrays that included a total of 2400 cDNAs. We found that chronic lithium treatment at a therapeutically relevant concentration decreased the expression of seven genes in lymphoblasts from lithium responders. Five of these candidate lithium-regulated genes, including alpha1B-adrenoceptor (alpha1B-AR), acetylcholine receptor protein alpha chain precursor (ACHR), cAMP-dependent 3',5'-cyclic phosphodiesterase 4D (PDE4D), substance-P receptor (SPR), and ras-related protein RAB7, were verified by Northern blotting analysis in lithium responders. None of these genes were regulated by lithium in healthy control subjects. When we compared the expression of these five genes between bipolar subjects and healthy control subjects at baseline, prior to lithium administration, we found that alpha1B-AR gene expression was higher in bipolar subjects than in healthy control subjects. Our findings indicate that alpha1B-AR may play an important role in the mechanism of action of lithium treatment.
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PMID:Identification of lithium-regulated genes in cultured lymphoblasts of lithium responsive subjects with bipolar disorder. 1473 34

Lithium ions' inhibition of adenylyl cyclase (AC) has not been previously studied for the newly discovered AC isoforms. COS7 cells were transfected with each of the nine membrane-bound AC isoforms cDNAs with or without D1- or D2-dopamine receptor cDNA. AC activity was measured as [3H]cAMP accumulation in cells pre-incubated with [3H]adenine followed by incubation with phosphodiesterase inhibitors together with either the D1 agonist SKF-82958 alone, or forskolin, in the presence or absence of the D2 agonist quinpirole. At 1 mm or 2 mm lithium inhibited only AC-V activity when the enzyme was stimulated by forskolin, a direct activator of AC. Lithium inhibited AC-V (by 50%), AC-VII (by 40%) and AC-II (by 25%) when stimulated via the D1 receptors, but did not affect the Ca2+-activated isoforms when stimulated by the Ca2+ ionophore A23187. Quinpirole inhibits AC via the Gi protein. Lithium did not affect quinpirole-inhibited FSK-activated AC-V activity nor did it affect superactivated AC-V or AC-I following the removal of quinpirole. The data suggest interference of lithium with transduction pathways mediated via AC-V or AC-VII; only the active conformation of these AC isoforms is inhibited by lithium; the inhibitory effect of lithium is abolished when the enzyme is superactivated. The marked inhibition of AC-V and AC-VII by lithium suggests that these two isoforms may be involved in mediating the mood-stabilizing effect of lithium.
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PMID:Lithium preferentially inhibits adenylyl cyclase V and VII isoforms. 1820 80

Lithium is still the mainstay in the treatment of affective disorders as a mood stabilizer. Lithium also shows some anticonvulsant properties. While the underlying mechanisms of action of lithium are not yet exactly understood, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of lithium is mediated via NO-cGMP pathway. Injection of a single effective dose of lithium chloride (25 mg/kg) intraperitoneally (i.p.) increased significantly the seizure threshold (P<0.01). The anticonvulsant properties of the effective dose of lithium were prevented by pre-treatment with the per se non-effective doses of L-ARG [the substrate for nitric oxide synthase; NOS] (30 and 50 mg/kg) or sildenafil [a phosphodiesterase 5 inhibitor] (10 and 20 mg/kg). L-NAME [a non-specific NOS inhibitor] (5, 15 and 30 mg/kg), 7-NI [a specific neural NOS inhibitor] (30 and 60 mg/kg) or MB [a guanylyl cyclase inhibitor] (0.5 and 1 mg/kg) augmented the anticonvulsant effect of a sub-effective dose of lithium (10 mg/kg, i.p.). Whereas several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of lithium. Our findings demonstrated that nitric oxide-cyclic GMP pathway could be involved in the anticonvulsant properties of the lithium chloride. In addition, the role of constitutive NOS versus inducible NOS is prominent in this phenomenon.
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PMID:Involvement of nitric oxide-cGMP pathway in the anticonvulsant effects of lithium chloride on PTZ-induced seizure in mice. 2030 10


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