Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of various dopaminergic agents and related drugs on the activity of the heat-stable inhibitor of cyclic AMP (cAMP)-dependent protein kinase (Walsh inhibitor) and on cAMP accumulation was studied in retinas of light- and dark-adapted rabbits. Both in dark- and light-adapted rabbits low doses of apomorphine increased the retinal Walsh inhibitor activity; high doses of the drug decreased the Walsh inhibitor activity in dark-adapted rabbits, but were without effect in light-adapted animals. S-Sulpiride antagonized the effect of low doses of apomorphine on the Walsh inhibitor activity, and, in contrast to haloperidol (which was effective), did not affect the action of a high apomorphine dose. Selective agonists of dopamine (DA) D2-receptor, quinpirole and bromocriptine, increased the retinal Walsh inhibitor activity in both light- and dark-adapted animals, a selective D1-agonist, SKF 38393, decreased the inhibitor activity in dark- and did not significantly modify it in light-adapted animals. In in vitro experiments, carried out in the presence of theophylline, DA and apomorphine increased cAMP accumulation in pieces of the rabbit retina through activation of D1-receptors. The action of DA, apomorphine, and SKF 38393, was significantly stronger in retinas of dark- than of light-adapted animals. Forskolin stimulated cAMP accumulation in a concentration-dependent manner, producing at 100 microM increases of cAMP levels by approximately 5-fold. DA and SKF 38393 did not significantly modulate the action of 10 microM forskolin, whereas apomorphine slightly decreased the forskolin effect. Of the two selective D2-receptor agonists, bromocriptine slightly decreased, and quinpirole had no effect on the forskolin action. The characteristics of the specific binding of [3H]spiroperidol were essentially the same in the retinas of dark- and light-adapted rabbits. Our data suggest that in light-adapted animals the D1-receptors, or the effector mechanisms for regulation of the Walsh inhibitor activity, may be desensitized. Our results suggest also that in the rabbit retina there are probably no D2-receptors coupled negatively to adenylate cyclase, although a pharmacologically similar class of DA receptors seems to be involved in regulation of the Walsh inhibitor activity (in a way independent on environmental lighting).
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PMID:Light modulates dopamine-regulated Walsh inhibitor activity and dopamine-dependent cyclic AMP accumulation in the rabbit retina. 198 30

This study examined the effect of chronic antipsychotic treatment on the NMDA-elicited changes in intracellular free Ca2+ concentration ([Ca2+]i) in the primary culture of rat frontal cortical neurons. Antipsychotics used in the study were chosen for their differential affinities at dopamine D2 receptors and sigma receptors. The potential involvement of protein kinases in this action of antipsychotics were also examined. Chronic treatment of cells with antipsychotics (sulpiride, clozapine, and chlorpromazine) which are known to be potent dopamine D2 receptor ligands, whereas possessing low or no appreciable affinity for sigma receptors, caused a dose-dependent potentiation of the NMDA-induced increase in [Ca2+]i. On the contrary, haloperidol, which is as potent a sigma receptor ligand as a dopamine D2 receptor ligand, did not affect the NMDA-elicited increase in [Ca2+]i. Sulpiride increased the maximum effect afforded by different concentrations of NMDA and shifted the dose-response curve of NMDA to the left (EC50 value from 12.5 microM to 1.39 microM). Consistent with sulpiride's affinity at dopamine D2 receptors, this action of sulpiride was stereoselective: S(-)-sulpiride was active whereas R(+)-sulpiride was inactive. Treatment of cells with dopamine (3 microM) tends to decrease the NMDA-induced increase in [Ca2+]i. Sulpiride at 1 microM totally abolished this action of dopamine and restored its potentiating action on the NMDA-induced increase in [Ca2+]i. Haloperidol, a potent dopamine D2 and sigma receptor ligand, did not affect the sulpiride's potentiating action on the NMDA-induced responses. On the other hand, chronic treatment of cells with a sigma receptor agonist, DTG, at a concentration producing no effect of its own (10 nM), led to an enhancement of the potentiating effect of sulpiride on NMDA-induced increase in [Ca2+]i. This action of DTG was abolished by haloperidol. Further, chronic, but not acute, treatment of cells with either a protein kinase inhibitor H-7 or a cAMP-dependent protein kinase (PKA) inhibitor H-89 abolished this effect of sulpiride on the NMDA-induced [Ca2+]i changes. These results indicate that the action of NMDA in the primary cortical neurons are regulated differently by ligands with differential affinities at dopamine D2 and sigma receptors. The results with protein kinase inhibitors indicate that the potentiation of NMDA responses by sulpiride involves intracellular biochemical events.
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PMID:Neuroleptics with differential affinities at dopamine D2 receptors and sigma receptors affect differently the N-methyl-D-aspartate-induced increase in intracellular calcium concentration: involvement of protein kinase. 1002 80

Antipsychotic drugs can regulate transcription of some genes, including those involved in regulation of hypothalamic-pituitary-adrenal (HPA) axis, whose activity is frequently disturbed in schizophrenic patients. However, molecular mechanism of antipsychotic drug action on the corticotropin-releasing hormone (CRH) gene activity has not been investigated so far. This study was undertaken to examine the influence of conventional and atypical antipsychotic drugs on the CRH gene promoter activity in differentiated Neuro-2A cell cultures stably transfected with a human CRH promoter fragment linked to the chloramphenicol acetyltransferase (CAT) reporter gene. It has been found that chlorpromazine (0.1-5.0 microM), haloperidol (0.5-5.0 microM), clozapine (1.0-5.0 microM), thioridazine (1.0-5.0 microM), promazine (5.0 and 10 microM), risperidone (5.0 and 10.0 microM), and raclopride (only at the highest used concentrations, ie 30 and 100 microM) present in culture medium for 5 days inhibited the CRH-CAT activity. Sulpiride and remoxipride had no effect. Since CRH gene activity is most potently enhanced by cAMP/protein kinase A pathway, the effect of antipsychotics on the forskolin-induced CRH-CAT activity was determined. Chlorpromazine (1.0-5.0 microM), haloperidol (1.0-5.0 microM), clozapine (1.0-5.0 microM), thioridazine (3.0 and 5.0 microM), and raclopride (30 and 100 microM), but not promazine, sulpiride, risperidone, and remoxipride, inhibited the forskolin-stimulated CRH gene promoter activity. A possible involvement of protein kinases in chlorpromazine and clozapine inhibitory action on CRH activity was also investigated. It was found that wortmannin (0.01 and 0.02 microM), an inhibitor of phosphatidylinositol 3-kinase (PI3-K), significantly attenuated the inhibitory effect of chlorpromazine and clozapine on CRH gene promoter activity. In line with these results, a Western blot study showed that these drugs increased phospho-Ser-473 Akt level, had no effect on total Akt, and decreased glycogen synthase kinase-3beta level. Additionally, we found that clozapine decreased protein kinase C (PKC) level and that its action on CRH activity was attenuated by PKC activator (TPA, 0.1 microM). The obtained results indicate that inhibition of CRH gene promoter activity by some antipsychotic drugs may be a molecular mechanism responsible for their inhibitory action on HPA axis activity. Clozapine and chlorpromazine action on CRH activity operates mainly through activation of the PI3-K/Akt pathway. Moreover, PKC-mediated pathway seems to be involved in clozapine action on CRH gene activity.
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PMID:Antipsychotic drugs inhibit the human corticotropin-releasing-hormone gene promoter activity in neuro-2A cells-an involvement of protein kinases. 1620 82