scholarly journals Changes in the activities of adenosine-metabolizing enzymes in six regions of the rat brain on chemical induction of hypothyroidism

1989 ◽  
Vol 261 (2) ◽  
pp. 667-672 ◽  
Author(s):  
D Mazurkiewicz ◽  
D Saggerson
Keyword(s):  
Neurotransmitter Release ◽  
Kinase Activity ◽  
Adenosine Kinase ◽  
Nucleotidase Activity ◽  
Chemical Induction ◽  
Metabolizing Enzymes ◽  
Adenosine Deaminase Activity ◽  
Membrane Bound ◽  
The Brain ◽  
Soluble Fractions

1. Rats (4 weeks old) were made hypothyroid by treatment with propylthiouracil and a low-iodine diet for a further period of 4 weeks. Synaptosomal membranes, myelin and 105,000 g soluble fractions were obtained from six regions of the brain. 2. Hypothyroidism resulted in 2-5-fold increases in membrane-bound 5′-nucleotidase activity in synaptosomal fractions obtained from cerebellum, cortex, striatum and hippocampus. By contrast, myelin 5′-nucleotidase activity was slightly increased only in the medulla oblongata. 3. Hypothyroidism did not change adenosine deaminase activity, but decreased adenosine kinase activity by approx. 40% in soluble fractions obtained from cerebellum, hippocampus, striatum and hypothalamus. 4. It is suggested that these changes in hypothyroidism, in particular the increases in 5′-nucleotidase activity, could enhance the neuromodulatory effect of adenosine to decrease neurotransmitter release.

scholarly journals Enzymes involved in adenosine metabolism in rat white and brown adipocytes. Effects of streptozotocin-diabetes, hypothyroidism, age and sex differences

1987 ◽  
Vol 245 (3) ◽  
pp. 881-886 ◽  
Author(s):  
Z Jamal ◽  
E D Saggerson
Keyword(s):  
Adenosine Deaminase ◽  
Streptozotocin Diabetes ◽  
Adenosine Kinase ◽  
Female Rats ◽  
Male Rats ◽  
Nucleotidase Activity ◽  
Brown Adipocytes ◽  
Cell Extracts ◽  
White Adipocytes ◽  
Adenosine Deaminase Activity

1. Adipocytes were isolated from epididymal white fat and interscapular brown fat of male rats, and activities of 5′-nucleotidase, adenosine deaminase and adenosine kinase were measured in cell extracts. 2. 5′-Nucleotidase activity in white adipocytes was increased in streptozotocin-diabetes, decreased in hypothyroidism and increased with age. That activity in brown adipocytes was unchanged in diabetes, decreased in hypothyroidism and increased with age. 5′-Nucleotidase activity was higher in white adipocytes from female rats. 3. Adenosine deaminase activity in white adipocytes was increased in diabetes, decreased in hypothyroidism and increased with age. That activity in brown adipocytes was decreased in diabetes and hypothyroidism. 4. Adenosine kinase activity in both cell types was unchanged in diabetes or hypothyroidism, but increased with age.

scholarly journals The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

2021 ◽  
Author(s):  
Marlaina R. Stocco ◽  
Ahmed A. El-Sherbeni ◽  
Bin Zhao ◽  
Maria Novalen ◽  
Rachel F. Tyndale
Keyword(s):  
Neurotransmitter Release ◽  
Behavioral Sensitization ◽  
Serotonin Release ◽  
Striatal Dopamine ◽  
Irreversible Inhibitor ◽  
Drug Concentrations ◽  
Metabolite Concentrations ◽  
The Brain

Abstract Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

Myristylation is required for Tyr-527 dephosphorylation and activation of pp60c-src in mitosis

1993 ◽  
Vol 13 (3) ◽  
pp. 1464-1470
Author(s):  
S Bagrodia ◽  
S J Taylor ◽  
D Shalloway
Keyword(s):  
Kinase Activity ◽  
Tyrosine Phosphatase ◽  
Src Kinase ◽  
Indirect Evidence ◽  
Membrane Localization ◽  
Wild Type ◽  
Src Tyrosine Kinase ◽  
Amino Terminal ◽  
Membrane Bound ◽  
Type C

The chicken proto-oncoprotein c-Src is phosphorylated by p34cdc2 during mitosis concomitant with increased c-Src tyrosine kinase activity. On the basis of indirect evidence, we previously suggested that this is caused by partial dephosphorylation at Tyr-527, the phosphorylation of which suppresses c-Src kinase activity. In support of this hypothesis, we now show that treatment of cells with a protein tyrosine phosphatase inhibitor, sodium vanadate, blocks the mitotic increase in Src kinase activity. Also, we show that an amino-terminal mutation that prevents myristylation (and membrane localization) of c-Src does not interfere with the p34cdc2-mediated phosphorylations but blocks both mitotic dephosphorylation of Tyr-527 (in kinase-defective Src) and stimulation of c-Src kinase activity. Furthermore, in unsynchronized cells, the kinase activity of nonmyristylated c-Src is suppressed by 60% relative to wild-type c-Src, presumably because of increased Tyr-527 phosphorylation. Consistent with this, the Tyr-527 dephosphorylation rate measured in cell homogenates is much higher for wild-type, myristylated c-Src than for nonmyristylated c-Src. Tyr-527 phosphatase activity was primarily associated with the nonsoluble subcellular fraction. These findings suggest that the phosphatase(s) that acts on Tyr-527 is membrane bound and indicate that membrane localization of c-Src is necessary for its mitotic activation by dephosphorylation of Tyr-527.

Drug metabolizing enzymes in the brain and cerebral microvessels

1991 ◽  
Vol 16 (1) ◽  
pp. 65-82 ◽  
Author(s):  
Alain Minn ◽  
Jean-François Ghersi-Egea ◽  
Rachel Perrin ◽  
Brigitte Leininger ◽  
Gérard Siest
Keyword(s):  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Cerebral Microvessels ◽  
The Brain

scholarly journals Is Phytomelatonin a New Plant Hormone?

Agronomy ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 95 ◽  
Author(s):  
Marino Arnao ◽  
Josefa Hernández-Ruiz
Keyword(s):  
Neurotransmitter Release ◽  
Plant Hormone ◽  
Great Similarity ◽  
Peripheral Organs ◽  
The Brain ◽  
Made In

Melatonin (N-acetyl-5-methoxytryptamine) is of particular importance as a chronobiological hormone in mammals, acting as a signal of darkness that provides information to the brain and peripheral organs. It is an endogenous synchronizer for both endocrine (i.e., via neurotransmitter release) and other physiological rhythms. In this work we will try to add to the series of scientific events and discoveries made in plants that, surprisingly, confirm the great similarity of action of melatonin in animals and plants. The most relevant milestones on the 25 years of phytomelatonin studies are presented, from its discovery in 1995 to the discovery of its receptor in plants in 2018, suggesting it should be regarded as a new plant hormone.

scholarly journals An Uncharacterized Member of the Ribokinase Family in Thermococcus kodakarensis Exhibits myo-Inositol Kinase Activity

2013 ◽  
Vol 288 (29) ◽  
pp. 20856-20867 ◽  
Author(s):  
Takaaki Sato ◽  
Masahiro Fujihashi ◽  
Yukika Miyamoto ◽  
Keiko Kuwata ◽  
Eriko Kusaka ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Three Dimensional ◽  
Fold Increase ◽  
Adenosine Kinase ◽  
Dimensional Structure ◽  
Uncharacterized Protein ◽  
Thermococcus Kodakarensis ◽  
Sugar Phosphates ◽  
Biochemical Analyses ◽  
Physiological Substrates

Here we performed structural and biochemical analyses on the TK2285 gene product, an uncharacterized protein annotated as a member of the ribokinase family, from the hyperthermophilic archaeon Thermococcus kodakarensis. The three-dimensional structure of the TK2285 protein resembled those of previously characterized members of the ribokinase family including ribokinase, adenosine kinase, and phosphofructokinase. Conserved residues characteristic of this protein family were located in a cleft of the TK2285 protein as in other members whose structures have been determined. We thus examined the kinase activity of the TK2285 protein toward various sugars recognized by well characterized ribokinase family members. Although activity with sugar phosphates and nucleosides was not detected, kinase activity was observed toward d-allose, d-lyxose, d-tagatose, d-talose, d-xylose, and d-xylulose. Kinetic analyses with the six sugar substrates revealed high Km values, suggesting that they were not the true physiological substrates. By examining activity toward amino sugars, sugar alcohols, and disaccharides, we found that the TK2285 protein exhibited prominent kinase activity toward myo-inositol. Kinetic analyses with myo-inositol revealed a greater kcat and much lower Km value than those obtained with the monosaccharides, resulting in over a 2,000-fold increase in kcat/Km values. TK2285 homologs are distributed among members of Thermococcales, and in most species, the gene is positioned close to a myo-inositol monophosphate synthase gene. Our results suggest the presence of a novel subfamily of the ribokinase family whose members are present in Archaea and recognize myo-inositol as a substrate.

scholarly journals Activity-dependent, homeostatic regulation of neurotransmitter release from auditory nerve fibers

2015 ◽  
Vol 112 (20) ◽  
pp. 6479-6484 ◽  
Author(s):  
Tenzin Ngodup ◽  
Jack A. Goetz ◽  
Brian C. McGuire ◽  
Wei Sun ◽  
Amanda M. Lauer ◽  
...  
Keyword(s):  
Auditory Nerve ◽  
Neurotransmitter Release ◽  
High Reliability ◽  
Downstream Processing ◽  
Nerve Fibers ◽  
Synaptic Activity ◽  
Quantal Size ◽  
Activity Dependent ◽  
The Brain ◽  
Homeostatic Response

Information processing in the brain requires reliable synaptic transmission. High reliability at specialized auditory nerve synapses in the cochlear nucleus results from many release sites (N), high probability of neurotransmitter release (Pr), and large quantal size (Q). However, high Pr also causes auditory nerve synapses to depress strongly when activated at normal rates for a prolonged period, which reduces fidelity. We studied how synapses are influenced by prolonged activity by exposing mice to constant, nondamaging noise and found that auditory nerve synapses changed to facilitating, reflecting low Pr. For mice returned to quiet, synapses recovered to normal depression, suggesting that these changes are a homeostatic response to activity. Two additional properties, Q and average excitatory postsynaptic current (EPSC) amplitude, were unaffected by noise rearing, suggesting that the number of release sites (N) must increase to compensate for decreased Pr. These changes in N and Pr were confirmed physiologically using the integration method. Furthermore, consistent with increased N, endbulbs in noise-reared animals had larger VGlut1-positive puncta, larger profiles in electron micrographs, and more release sites per profile. In current-clamp recordings, noise-reared BCs had greater spike fidelity even during high rates of synaptic activity. Thus, auditory nerve synapses regulate excitability through an activity-dependent, homeostatic mechanism, which could have major effects on all downstream processing. Our results also suggest that noise-exposed bushy cells would remain hyperexcitable for a period after returning to normal quiet conditions, which could have perceptual consequences.

scholarly journals Adenosine kinase inhibition promotes proliferation of neural stem cells after traumatic brain injury

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Hoda M Gebril ◽  
Rizelle Mae Rose ◽  
Raey Gesese ◽  
Martine P Emond ◽  
Yuqing Huo ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Brain Injury ◽  
Neural Stem Cell ◽  
Adenosine Kinase ◽  
Health Concern ◽  
Stem Cell Proliferation ◽  
Neural Stem Cell Proliferation ◽  
The Brain

Abstract Traumatic brain injury (TBI) is a major public health concern and remains a leading cause of disability and socio-economic burden. To date, there is no proven therapy that promotes brain repair following an injury to the brain. In this study, we explored the role of an isoform of adenosine kinase expressed in the cell nucleus (ADK-L) as a potential regulator of neural stem cell proliferation in the brain. The rationale for this hypothesis is based on coordinated expression changes of ADK-L during foetal and postnatal murine and human brain development indicating a role in the regulation of cell proliferation and plasticity in the brain. We first tested whether the genetic disruption of ADK-L would increase neural stem cell proliferation after TBI. Three days after TBI, modelled by a controlled cortical impact, transgenic mice, which lack ADK-L (ADKΔneuron) in the dentate gyrus (DG) showed a significant increase in neural stem cell proliferation as evidenced by significant increases in doublecortin and Ki67-positive cells, whereas animals with transgenic overexpression of ADK-L in dorsal forebrain neurons (ADK-Ltg) showed an opposite effect of attenuated neural stem cell proliferation. Next, we translated those findings into a pharmacological approach to augment neural stem cell proliferation in the injured brain. Wild-type C57BL/6 mice were treated with the small molecule adenosine kinase inhibitor 5-iodotubercidin for 3 days after the induction of TBI. We demonstrate significantly enhanced neural stem cell proliferation in the DG of 5-iodotubercidin-treated mice compared to vehicle-treated injured animals. To rule out the possibility that blockade of ADK-L has any effects in non-injured animals, we quantified baseline neural stem cell proliferation in ADKΔneuron mice, which was not altered, whereas baseline neural stem cell proliferation in ADK-Ltg mice was enhanced. Together these findings demonstrate a novel function of ADK-L involved in the regulation of neural stem cell proliferation after TBI.

scholarly journals Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Andrew E. Arrant ◽  
Jonathan R. Roth ◽  
Nicholas R. Boyle ◽  
Shreya N. Kashyap ◽  
Madelyn Q. Hoffmann ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Posttranslational Modifications ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Inferior Frontal Gyrus ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Wild Type ◽  
Metabolizing Enzymes ◽  
Dementia Patients ◽  
The Brain

AbstractLoss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn−/− mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing.

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