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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of lithium on calmodulin-stimulated adenylate cyclase activity has been studied in vitro and after chronic treatment. Chronic lithium treatment decreased calcium-calmodulin-stimulated adenylate cyclase activity in rat cortical membranes, while no effect was observed on GTP-stimulated activity. Lithium in vitro inhibited adenylate cyclase activity stimulated by isoprenaline, GTP or calcium-calmodulin. Calcium-calmodulin-stimulated activity was more sensitive to lithium (2 mM) than isoprenaline- and GTP-stimulated activities (5 mM) and activities by these agents combined. Lithium had no effect on the unstimulated enzyme activity. The inhibitory effect of lithium in vitro on calcium-calmodulin-stimulated adenylate cyclase activity was antagonized by magnesium. The inhibition induced by lithium in vitro on the GTP-stimulated adenylate cyclase activity was increased by substituting manganese for magnesium in the assay media. Furthermore, the manganese-stimulated activity was also reduced by lithium. The latter effect was not observed in calmodulin-depleted membranes, but the inhibitory effect of lithium could be restored by addition of exogenous calmodulin. The present results suggest that lithium might influence the interaction of calmodulin with the enzyme and/or interfere with the divalent cation site(s) on the adenylate cyclase system.
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PMID:Effects of lithium on calmodulin-stimulated adenylate cyclase activity in cortical membranes from rat brain. 303 39

The effects of lithium on the activity of adenylate cyclase stimulated by hormones, which act via the stimulatory guanine nucleotide binding subunit (Ns), by forskolin, which acts at the catalytic subunit, and by guanyl-5'-yl imidodiphosphate (GppNHp), which locks the enzyme into a permanently active state, have been compared in a preparation of membranes from the cerebral cortex of the rat. Lithium ions (Li+) in vitro at 2-4 mM inhibited cyclase stimulated by isoproterenol and forskolin, but had no effect on the inhibition induced by met-enkephalin of the enzyme stimulated by forskolin, mediated by the inhibitory guanine nucleotide binding subunit (Ni). Inhibition of the activity stimulated by forskolin and GppNHp was competitive with magnesium (Mg++). In a preparation of slices of cerebral cortex Li+ at 1-2 mM inhibited accumulation of cyclic AMP stimulated by forskolin in a non-competitive manner. In a preparation of membranes from the caudate nucleus, Li+ at 2-4 mM inhibited dopamine-stimulated adenylate cyclase, but this effect was not observed in the presence of additional sodium (Na+). Membranes prepared from animals fed with Li+ to give a mean serum level of 0.52 mM and a mean brain level of 1.32 mM, showed a reduced response to manganese (Mn++), forskolin, isoproterenol and GppNHp in the cerebral cortex, but no change in the degree of activation of the enzyme by either dopamine or forskolin, or the degree of inhibition by met-enkephalin, in the caudate nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of lithium in vitro and ex vivo on components of the adenylate cyclase system in membranes from the cerebral cortex of the rat. 303 12

In single cortical collecting tubules (CCT) of the rabbit, guanosine 5'-triphosphate (GTP) increased the arginine vasopressin (AVP)-stimulated adenylate cyclase (AC) by 60% (P less than 0.05). In contrast, guanosine 5' O-(2-thio)-diphosphate (GDP-beta S), a competitive inhibitor of GTP action on the stimulatory guanine regulatory protein (Ns), reduced the AVP-stimulated AC activity by 72% (P less than 0.001), indicating the presence of endogenous GTP in the cells under study. That inhibitory effect was reversed by the addition of GTP to the incubation medium. In isolated perfused CCT, cholera toxin (CT) induced a significant increase in water permeability in the absence of AVP. In contrast, Bordetella pertussis toxin (BPT) did not modify the low AVP-independent water permeability. Lithium, an inhibitor of the hydrosmotic action of AVP, also inhibits the hydrosmotic action of CT by 70% (P less than 0.05) but not that of forskolin. The conclusions of the present study are Ns is required for AVP stimulation of AC in the CCT; Ns is functionally active in this system as evidenced by the hydrosmotic effect of CT; the lack of effect of BPT suggests that the low AVP-independent water permeability in the CCT is not the result of a tonic inhibition of the AC operating through the inhibitory guanine nucleotide regulatory protein; and the inhibition by lithium of the hydrosmotic action of AVP in the CCT appears to involve an interaction with the regulatory proteins (probably Ns) or with their binding to the catalytic unit of AC.
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PMID:Mechanisms of lithium-vasopressin interaction in rabbit cortical collecting tubule. 310 54

Lithium is a unique drug with therapeutic as well as prophylactic value for both manic and depressive phases of manic-depressive illness. The precise mechanisms of its clinical efficacy remain unknown, but there are two main theories of its biochemical action. One proposes that lithium inhibits adrenergically activated adenylate cyclase function whereas the other suggests that it inhibits phosphatidyl inositol turnover, which is known to be activated by cholinergic agonists. Neither mechanism alone, however, can explain both the antimanic and antidepressant effects of lithium. Because of the pivotal role of G proteins in post-receptor information transduction, we have investigated the interaction of lithium with G protein function. Lithium at therapeutically efficacious concentrations completely blocked both adrenergic and cholinergic agonist-induced increases in [3H]GTP binding to membranes from rat cerebral cortex, in both in vitro and ex vivo experiments. The same lithium treatments also abolished guanine nucleotide modulation of agonist binding. Our findings suggest G proteins (Gs and Gi or Go) as the molecular site of action for both the antimanic and antidepressant effects of lithium.
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PMID:Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex. 334 Jan 89

Blood and urine samples were collected at timed intervals for up to 120 min after the start of a 30-min infusion of 30 IU bovine parathyroid hormone (PTH) into 6 normal male subjects. Infusions were performed before and after 7 days' treatment with lithium carbonate. A highly significant increase in the maximum renal tubular reabsorption capacity for calcium (TmCa/GFR) from 2.02 +/- 0.04 to 2.17 +/- 0.07 mmol/l (p less than 0.02) produced a significant rise in plasma calcium. Lithium had no effect on basal fasting PTH or nephrogenous cyclic AMP (cAMP). Changes in nephrogenous cAMP and TmP/GFR in response to PTH were not altered by lithium. The absorption of 47Ca following an oral calcium load was increased in 5 out of 6 subjects also treated for 1 week with lithium. These results suggest that lithium has a direct effect on calcium transport, both at the level of the renal tubule and the gut, which is not mediated by stimulation of parathyroid activity or via modification of PTH-stimulated adenylate cyclase.
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PMID:Effect of lithium on the metabolic response to parathyroid hormone. 358 84

The action of lithium on calcium-calmodulin-activated and forskolin-activated catalytic unit of adenylate cyclase has been studied. The catalytic unit was solubilized from rat brain and separated from the guanine nucleotide binding protein by gel filtration. Calcium-calmodulin-stimulated and forskolin-stimulated catalytic unit activities were inhibited in the presence of 2 mM and 1 mM of lithium, respectively. No inhibitory effect was observed on the basal activity. The inhibitory effect of lithium on the stimulated activities was antagonized by magnesium. Lithium did not influence the interaction of the enzyme substrate (ATP) with the catalytic unit. The present results indicate that lithium interacts directly with the catalytic unit of the adenylate cyclase system. In the neuron, lithium might interfere with a divalent cation site on the catalytic unit.
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PMID:Mode of action of lithium on the catalytic unit of adenylate cyclase from rat brain. 358 21

Adenyl cyclase activity in intestinal membranes has been studied during development in the rabbit fetus from fetal day 17 to 10 days postnatally and in the human fetus from the 10th to the 17th wk of gestation. In the rabbit, the enzyme was already present by fetal day 17 and showed a fourfold peak rise in specific activity by 22 days. By 28 days, the specific activity had fallen toward adult levels and remained constant throughout gestation and the 1st wk of life. Fluoridestimulated activity showed a similar curve, and was 2.5-5 times the basal values. Activities in jejunum and ileum were comparable at all time points studied. Phosphodiesterase activity did not change during gestation. When fetal intestinal segments were incubated in vitro with purified cholera enterotoxin, adenyl cyclase activity in subsequently prepared membranes was increased two- to threefold. This level was not regularly further elevated by fluoride ion. Lithium ion inhibited both the basal and fluoride-stimulated enzyme activity in membranes prepared from rabbit fetuses at term. Lactase activity (reflecting the development of the microvilli) in either whole intestinal homogenates or in the membrane fractions showed a differnet pattern of development, with a rise beginning on fetal day 24 and a plateau just after birth. In intestinal membranes prepared from human fetuses, the activity of both basal and fluoride-stimulated adenyl cyclase tripled from the 10th to the 17th wk of gestation. The data both in the rabbit and in man show that intestinal adenyl cyclase is capable of responding to cholera enterotoxin quite early in gestation. In the rabbit, this occurs before the time of appearance or ville or of an enzyme marker (lactase) for microville. The results support the concept that adenyl cyclase is present in plasma membrane other than the brush border.
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PMID:Development of intestinal adenyl cyclase and its response to cholera enterotoxin. 435 79

Lithium, an adenylate cyclase inhibitor, stimulates a variety of in vitro indices of immune function, including proliferation of lymphocytes in response to mitogens, rosette formation by T-cells and phagocytosis by macrophages. Lithium enhances these immunologic responses at concentrations comparable to those achieved in patients receiving lithium for treatment of manic-depressive disorders. Lithium may prove to have important therapeutic applications as an immune adjuvant, particularly in immune deficiency states associated with excessive C-AMP production.
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PMID:Lithium as an immunologic adjuvant. 624 27

Cell surface receptors receive, transduce and relay a variety of environmental signals. These phenomena, which have been extensively characterized in non-lymphoid cells, also appear to play a crucial role in dictating the degree of lymphocyte responsiveness. The nature of these regulatory events is only beginning to be unraveled but the adenylate cyclase-cyclic AMP axis appears to be one of the important controlling systems. Lithium appears to be as important a modulator of lymphocyte responsiveness as previously shown for a variety of other cells and the mechanism of action, in general, is consistent with its role as a putative blocker of adenylate cyclase activation. Indeed, lithium may exert its role as a regulator of lymphocyte responsiveness by acting on specific lymphocyte subpopulations. Direct proof for this is still wanting and consideration of its capacity for action as an imperfect substitute for normal extra- or intracellular cations or on the physiochemical state of the plasma membrane is necessary. Nevertheless, these studies indicate the validity of using lithium for assessing the role of the lymphocyte adenylate cyclase-cyclic AMP system in the generation and expression of regulatory signals leading to modulation of the immune system.
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PMID:Characterization of lithium effects on two aspects of T-cell function. 625 Mar 37

Human CSF cyclic nucleotides do not distinguish manic-depresive patients or schizophrenic patients from controls, although a "high CSF cyclic AMP" subgroup of poor-prognosis schizophrenics is still under investigation. Neuroleptic therapy raises CSF cyclic GMP and lowers CSF cyclic AMP, at least in the responder subgroup of a clinically heterogeneous patient population when neuroleptics that are good adenylate cyclase inhibitors in vitro are used in the treatment. This is consistent with the concept that neuroleptic treatment in humans involves blockade of dopamine neurotransmission. Attempts to correlate the decline in CSF cyclic AMP concentration with clinical improvement may be important. Lithium treatment does not alter the level of CSF cyclic AMP, which probably derives largely from dopamine-related neurotransmission that lithium does not affect. However, the plasma cyclic AMP response to epinephrine is inhibited by lithium at therapeutic doses in vivo after chronic treatment. The lithium effect is somewhat specific in that the glucagon-stimulated rise in plasma cyclic AMP is not affected. The results in clinical experiments support the theory that norepinephrine-sensitive adenylate cyclase inhibition in brain is involved in lithium action. Research to attempt to distinguish lithium-responsive from lithium nonresponsive patients on the basis of sensitivity to lithium inhibition of the epinephrine-induced rise in plasma cyclic AMP is of considerable potential practical importance.
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PMID:Cyclic nucleotides in mental disorder. 625 Mar 53


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