Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoid excess is associated with hippocampal neuronal dysfunction and loss, mainly affecting CA1. Degeneration of both cholinergic and serotonergic (5-HT) hippocampal afferents is prominent in aged rats and Alzheimer's disease. Lesions of these individual pathways alter hippocampal expression of mineralocorticoid (MR) and glucocorticoid (GR) receptor mRNAs; both transcripts are increased by cholinergic lesions, but markedly decreased by serotonergic denervation. In the present study we found that combined medial septal cholinergic and central 5-HT lesions increase hippocampal GR mRNA expression, specifically in CA1 and CA2 subfields, whereas MR mRNA expression was similar to controls. Thus the effects of the cholinergic lesion, at least upon GR gene expression, appear to predominate while the effects of the lesions upon MR gene expression were additive. Increased hippocampal GR gene expression per neuron may increase hippocampal neuronal vulnerability with age or disease.
Brain Res Mol Brain Res 1994 Nov
PMID:Increased glucocorticoid receptor gene expression in the rat hippocampus following combined serotonergic and medial septal cholinergic lesions. 787 48

Trimethyltin (TMT) destroys specific subfields of the hippocampus in the rat. TMT also increases choline acetyltransferase (ChAT) activity in CA1 of Ammon's horn and the outer molecular layer of the dentate gyrus. This observation suggests that axonal sprouting occurs in the cholinergic septohippocampal system in response to TMT. However, neither does-response nor time course data are available for the effects of TMT on this enzyme. The effects of three dose levels of TMT on ChAT activity in CA1 and the dentate gyrus were determined in Experiment 1 and ChAT activity in these two areas was measured at six time points following exposure to TMT in Experiment 2. Only the highest dose of TMT (6 mg/kg) significantly increased ChAT activity. ChAT activity in the dentate gyrus increased significantly by 3 d after administration and continued to increase until 21 d after exposure. A significant increase was not observed in CA1 until 7 d after exposure to TMT. Asymptotic levels were still reached at d 21. These results indicate a steep dose-response curve for TMT-induced changes in ChAT activity in the hippocampal formation and that this marker of cholinergic activity is more sensitive to perturbation by TMT in the dentate gyrus than Ammon's horn.
Mol Chem Neuropathol 1994 Sep
PMID:Effects of trimethyltin (TMT) on choline acetyltransferase activity in the rat hippocampus. Influence of dose and time following exposure. 789 29

Adult male Long-Evans rats were given 6 mg/kg trimethyltin (TMT). Rats were killed 1, 3, 7, 14, 21, 35, or 60 d later. An untreated control group was included. Brain sections were processed using film autoradiography to visualize in the hippocampus either total muscarinic receptor binding ([3H]quinuclidinyl benzilate; [3H]QNB), or M1 receptors ([3H]pirenzepine; [3H]PZ), or M2 receptors ([3H]oxotremorine-M; [3H]OXO-M). A reduction in [3H]QNB binding was found in CA1 and CA3c 7 d after TMT, but not in CA3a, b, or the dentate gyrus. [3H]PZ binding was decreased throughout Ammon's horn by 14 d after treatment. [3H]OXO-M binding decreased 1 d after exposure in CA1 and in all subfields of Ammon's horn by d 3. Neither [3H]PZ or [3H]OXO-M binding decreased in the dentate gyrus of TMT-treated rat at any time point. The temporal patterns of receptor loss may be explicable by reference to timing of fiber and cell body degeneration reported in previous studies and the regional differences may account for discrepancies between reports of either substantial decreases or no loss in hippocampal muscarinic receptors after TMT exposure.
Mol Chem Neuropathol 1994 Sep
PMID:The effect of time following exposure to trimethyltin (TMT) on cholinergic muscarinic receptor binding in rat hippocampus. 789 30

We studied the localizations of alpha 1 and beta 1 subunits of soluble guanylate cyclase using in situ hybridization. The beta subunit was widely distributed in most neurons throughout the brain, with different levels of expression. The alpha 1 subunit was also distributed throughout the brain; however, it was located in more limited regions. Both subunits were expressed markedly in the glomerular layer of the olfactory bulb, dorsal and ventral striatum, and several regions in the brainstem. Regions with little or no alpha 1 subunit expression, but with marked expression of the beta 1 subunit included the olfactory bulb except for the glomerular layer, pyramidal cell layer in CA1 and granular cell layer in the dentate gyrus of the hippocampus, and many brainstem nuclei. The above regions expressing both subunits are suggested to contain active soluble guanylate cyclase as a target for nitric oxide, and thus may be involved in cellular signal transduction.
Brain Res Mol Brain Res 1993 Dec
PMID:Localizations of alpha 1 and beta 1 subunits of soluble guanylate cyclase in the rat brain. 790 52

The redistribution of glutamate and GABA in postischemic brains was examined immunocytochemically using the gerbil model of unilateral 1 h cerebral ischemia. In the cerebral neocortex, the majority of neurons underwent recovery processes after 5 h of recirculation, while neurons in the hippocampus were irreversibly damaged. Glutamate-like immunoreactivity (LI) was highly increased in the degenerating hippocampal CA3 pyramidal cells after recirculation, while in the neocortex and the hippocampal CA1 sector, the pyramidal cells showed only slightly increased glutamate-LI. GABA-LI-positive punctae in the neuropil, corresponding to neuronal processes of GABAergic neurons, were accentuated after recirculation both in the cerebral neocortex and the hippocampus. Although the astrocytes on the nonischemic side showed neither glutamate-LI nor GABA-LI, the swollen astrocytes and their foot processes, which were observed after recirculation, often showed strong glutamate-LI and GABA-LI. These data suggest (1) the accumulation of glutamate or glutamate-like substances, especially in the CA3 pyramidal cells, (2) the excitation of the GABAergic neurons and their subsequent uptake of GABA, and (3) the sequestration of the extracellular neurotransmitters by astrocytes in the postischemic period.
Mol Chem Neuropathol 1994 May
PMID:Redistribution of glutamate and GABA in the cerebral neocortex and hippocampus of the Mongolian gerbil after transient ischemia. An immunocytochemical study. 791 66

Prolonged benzodiazepine treatment of rats results in anticonvulsant tolerance in vivo. Studies of in vitro hippocampal slices following 1 wk flurazepam administration show reduced GABA-mediated inhibition in the CA1 region, and a decrease in GABAA agonist and benzodiazepine potency to inhibit CA1 pyramidal cell-evoked responses. To investigate the molecular basis of benzodiazepine tolerance in the hippocampus, in situ hybridization techniques were used to evaluate the expression of the mRNAs for the alpha 1, alpha 5, and gamma 2 subunits of the GABAA receptor in the hippocampal formation and frontal cortex of chronic flurazepam-treated rats. A discretely localized decrease in alpha 1, but not alpha 5 or gamma 2 mRNA expression was found in the CA1 region (35-40%) and in layers II-III and IV of cortex (50-60%) 2 d after cessation of flurazepam treatment. The decrease in the expression of alpha 1 subunit mRNA in cortex is similar to that reported following other chronic benzodiazepine treatment regimens. This is the first report of a reduction in alpha 1 subunit mRNA expression in the hippocampal formation.
J Mol Neurosci 1993
PMID:Expression of alpha 1, alpha 5, and gamma 2 GABAA receptor subunit mRNAs measured in situ in rat hippocampus and cortex following chronic flurazepam administration. 791 36

N-unsubstituted sulfonamide drugs are widely used for opthalmic disorders. Inhibition of carbonic anhydrase enzyme is believed to be the chief reason for their therapeutic effects. Structures of three such sulfonamide drugs complexed to human carbonic anhydrase I enzyme (HCAI) refined crystallographically at 2 A resolution are reported here. The drug molecules are all bound in the active site of the enzyme, but among themselves show differences in the orientations of the sulfamido groups interacting with the essential zinc ion in the active site. The activity linked solvent molecule coordinated to zinc in the native enzyme is displaced by all the three sulfonamides. The active site loop of Leu198, Thr199 and His200 has been identified to be important for binding of the drug molecules due to their appreciable atomic displacements and intra-molecular hydrogen bonds arising out of their interactions with the sulfonamides. These interactions along with active site charge requirements are proposed to be responsible for the orientational differences of the sulfamido groups and also for differences in the inhibitory powers of the drugs. A hydrogen bond network involving solvent molecules and active site residues His200 and His67 amongst others in the native enzyme, is disrupted upon binding of methazolamide but not in the other two sulfonamides. This is the first crystallographic evidence of the possible involvement of His200 in the inhibition of HCAI. An important role of Thr199 in distinguishing between the substrate and inhibitor binding modes of HCO3- to the enzyme at high pH is also inferred.
J Mol Biol 1994 Oct 21
PMID:Drug-protein interactions. Refined structures of three sulfonamide drug complexes of human carbonic anhydrase I enzyme. 793 56

The distribution of cells expressing mRNA encoding a vasopressin V1a receptor (V1aR) was examined in Long-Evans male and female rats by in situ hybridization using a [35S]cRNA probe. Specific hybridization to the vasopressin V1aR mRNA was evident in cells of the frontal cortex, piriform cortex, internal granular layer and the medial, dorsal, ventral and lateral portion of the anterior olfactory nucleus, zona limitans of the islands of Calleja, suprachiasmatic nucleus, CA1, CA2, CA3 and dentate gyrus of the hippocampus, paraventricular hypothalamic nucleus, ventromedial hypothalamic nucleus, arcuate nucleus, lateral habenular nucleus, and the molecular and granular cell layers of the cerebellum. The cerebellum, olfactory nucleus and the dentate gyrus appeared to be the most intensely labeled areas, while all other areas exhibited a lower level of expression. The anatomical distribution and the amount (as measured by optical density) of V1aR mRNA labeling was identical between male and female rats. This indicates that unlike the vasopressin gene itself, the expression of the vasopressin V1aR mRNA does not exhibit sexual dimorphism. These data demonstrate a wide spread distribution in the expression of the vasopressin V1aR mRNA in the CNS of male and female rats. This information on the anatomical distribution of the V1aR mRNA when combined with data concerning the anatomical distribution of the V1a binding sites, provides new information on the possible pre- and post-synaptic location of these neuropeptide receptors.
Brain Res Mol Brain Res 1994 Jul
PMID:Distribution of messenger RNA for the vasopressin V1a receptor in the CNS of male and female rats. 796 46

The effects of kainic acid (15 mg/kg i.p.) on alpha subunits of the Gs and Go protein mRNA levels in the rat hippocampal formation were investigated. An in situ hybridization study showed an increase in the Gs alpha mRNA level in the dentate gyrus at 3 h (by ca. 17%), 24 h (by ca. 75%), 72 h (by ca. 89%) and 30 days (by ca. 59%) after kainic acid administration. An emulsion autoradiography revealed enhancement in the Gs alpha mRNA signal intensity over granular cells of the dentate gyrus and over some hilar cells adjacent to the granule cell layer, most likely in GABA interneurons. The Gs alpha mRNA showed a slight tendency to increase in the CA1 and CA3 pyramidal cell layers at 3 h after kainic acid administration, but it decreased after 24 h, 72 h and 30 days. The latter decrease correlated well with the pyramidal cells loss in those areas. Kainic acid differently influenced the Go alpha mRNA level in the dentate gyrus: it had no effect after 3 h, while after 24 h the mRNA level tended to decrease (by ca. 16%); then it increased after 72 h (by ca. 20%) and, to a lesser extent, after 30 days (by ca. 12%). The Go alpha mRNA level in CA1 and CA3 tended to decrease at 3 h after kainic acid administration; the signal completely disappeared after 24, 72 h as well as after 30 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1994 Jul
PMID:Seizure-induced expression of G proteins in the rat hippocampus. 796 78

Studies carried out with mammals and invertebrates suggest that Ca(2+)-sensitive adenylyl cyclases may be important for neuroplasticity. Long-term potentiation in the hippocampus requires increases in intracellular Ca2+ which are accompanied by elevated cyclic AMP (cAMP). Furthermore, activation of cAMP-dependent protein kinase is required for the late stage of long-term potentiation in the CA1 region of the hippocampus, which is also sensitive to inhibitors of transcription. Therefore, some forms of synaptic plasticity may require coordinate regulation of transcription by Ca2+ and cAMP. In this study, we demonstrate that the expression of type I adenylyl cyclase in HEK-293 cells allows Ca2+ to stimulate reporter gene activity mediated through the cAMP response element. Furthermore, simultaneous activation by Ca2+ and isoproterenol caused synergistic stimulation of transcription in HEK-293 cells and cultured neurons. We propose that Ca2+ and neurotransmitter stimulation of type I adenylyl cyclase may play a role in synaptic plasticity by generating optimal cAMP signals for regulation of transcription.
Mol Cell Biol 1994 Dec
PMID:Type I adenylyl cyclase functions as a coincidence detector for control of cyclic AMP response element-mediated transcription: synergistic regulation of transcription by Ca2+ and isoproterenol. 796 63


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