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Dimethyl amiloride improves glucose homeostasis in mouse models of type 2 diabetes.
Gunawardana SC, Head WS, Piston DW
(2008) Am J Physiol Endocrinol Metab 294: E1097-108
MeSH Terms: Amiloride, Amino Acids, Cyclic, Animals, Arginine, Blood Glucose, Diabetes Mellitus, Type 2, Disease Models, Animal, Drug Synergism, Homeostasis, Hydrogen-Ion Concentration, Insulin, Insulin Secretion, Insulin-Secreting Cells, Keto Acids, Ketoglutarate Dehydrogenase Complex, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, NG-Nitroarginine Methyl Ester, Nitric Oxide Synthase Type I, Sodium-Calcium Exchanger
Show Abstract · Added November 1, 2012
Dimethyl amiloride (DMA) enhances insulin secretion in the pancreatic beta-cell. DMA also enhances time-dependent potentiation (TDP) and enables TDP to occur in situations where it is normally absent. As we have demonstrated before, these effects are mediated in part through inhibition of neuronal nitric oxide synthase (nNOS), resulting in increased availability of arginine. Thus both DMA and arginine have the potential to correct the secretory defect in diabetes by enabling or enhancing TDP. In the current study we have demonstrated the ability of these agents to improve blood glucose homeostasis in three mouse models of type 2 diabetes. The pattern of TDP under different conditions indicates that inhibition of NOS is not the only mechanism through which DMA exerts its positive effects. Thus we also have explored another possible mechanism through which DMA enables/enhances TDP, via the activation of mitochondrial alpha-ketoglutarate dehydrogenase.
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23 MeSH Terms
Anaplerotic input is sufficient to induce time-dependent potentiation of insulin release in rat pancreatic islets.
Gunawardana SC, Liu YJ, Macdonald MJ, Straub SG, Sharp GW
(2004) Am J Physiol Endocrinol Metab 287: E828-33
MeSH Terms: Acetyl Coenzyme A, Amino Acids, Amino Acids, Cyclic, Analysis of Variance, Animals, Calcium, Citric Acid Cycle, Enzyme Activation, Glucose, In Vitro Techniques, Insulin, Insulin Secretion, Islets of Langerhans, Ketoglutaric Acids, Male, Mitochondria, Rats, Rats, Wistar, Signal Transduction, Stimulation, Chemical, Up-Regulation
Show Abstract · Added November 1, 2012
Nutrients that induce biphasic insulin release, such as glucose and leucine, provide acetyl-CoA and anaplerotic input in the beta-cell. The first phase of release requires increased ATP production leading to increased intracellular Ca(2+) concentration ([Ca(2+)](i)). The second phase requires increased [Ca(2+)](i) and anaplerosis. There is strong evidence to indicate that the second phase is due to augmentation of Ca(2+)-stimulated release via the K(ATP) channel-independent pathway. To test whether the phenomenon of time-dependent potentiation (TDP) has similar properties to the ATP-sensitive K(+) channel-independent pathway, we monitored the ability of different agents that provide acetyl-CoA and anaplerotic input or both of these inputs to induce TDP. The results show that anaplerotic input is sufficient to induce TDP. Interestingly, among the agents tested, the nonsecretagogue glutamine, the nonhydrolyzable analog of leucine aminobicyclo[2.2.1]heptane-2-carboxylic acid, and succinic acid methyl ester all induced TDP, and all significantly increased alpha-ketoglutarate levels in the islets. In conclusion, anaplerosis that enhances the supply and utilization of alpha-ketoglutarate in the tricarboxylic acid cycle appears to play an essential role in the generation of TDP.
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21 MeSH Terms
NMDA and beta1-adrenergic receptors differentially signal phosphorylation of glutamate receptor type 1 in area CA1 of hippocampus.
Vanhoose AM, Winder DG
(2003) J Neurosci 23: 5827-34
MeSH Terms: Adrenergic Antagonists, Adrenergic beta-1 Receptor Antagonists, Adrenergic beta-Agonists, Amino Acids, Cyclic, Animals, Cyclic AMP-Dependent Protein Kinases, Dose-Response Relationship, Drug, Excitatory Postsynaptic Potentials, Hippocampus, In Vitro Techniques, Long-Term Potentiation, Male, Mice, Mice, Inbred C57BL, N-Methylaspartate, Neuronal Plasticity, Phosphorylation, Receptors, AMPA, Receptors, Adrenergic, beta-1, Receptors, N-Methyl-D-Aspartate, Signal Transduction
Show Abstract · Added May 19, 2014
Glutamatergic synaptic transmission is mediated primarily through the AMPA-type glutamate receptor (AMPAR); the regulation of this receptor underlies many forms of synaptic plasticity. In particular, phosphorylation of GluR1, an AMPAR subunit, by PKA at serine 845 (S845) increases peak open channel probability and is permissive for both the synaptic expression of the receptor and NMDA-receptor (NMDAR)-dependent long-term potentiation (LTP). Robust NMDAR activation activates PKA as well as other signaling enzymes; however, we find that maximal NMDAR activation dephosphorylates GluR1 at the PKA site S845. Coincident inhibition of phosphatases blocks NMDAR-induced dephosphorylation of S845, but surprisingly does not promote PKA phosphorylation at this site. However, we find that phosphorylation of S845 is increased by the activation of a Gs-coupled receptor, the beta1-adrenergic receptor. Interestingly, this divergent signaling occurs despite a more robust coupling of the NMDAR to cAMP generation. In addition, NMDAR activation plays a dominant role in S845 regulation, because activation of beta1AR after NMDAR activation has no detectable effect on S845 phosphorylation. These data (1) demonstrate highly specific coupling between these receptors and this substrate, (2) provide an example of a substrate critical in NMDAR-dependent LTP that is incompletely regulated by the NMDAR, and (3) highlight the importance of identifying the physiological signals that regulate these critical synaptic substrates.
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21 MeSH Terms
Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a second family.
Maller A, Hyland K, Milstien S, Biaggioni I, Butler IJ
(1997) J Child Neurol 12: 349-54
MeSH Terms: 5-Hydroxytryptophan, Amino Acids, Cyclic, Aromatic-L-Amino-Acid Decarboxylases, Biogenic Monoamines, Child, Preschool, Consanguinity, Developmental Disabilities, Homovanillic Acid, Humans, Hydroxyindoleacetic Acid, Iran, Levodopa, Longitudinal Studies, Male, Methoxyhydroxyphenylglycol, Muscle Hypotonia, Pyridoxine
Show Abstract · Added December 10, 2013
Aromatic L-amino acid decarboxylase deficiency is an inborn error of metabolism that leads to combined serotonin and catecholamine deficiency, first described by Hyland et al in 1990. The clinical features, biochemical findings, and treatment of the second family with this condition are reported. Our male patient presented with developmental delay, extreme hypotonia, oculogyric crises, and irritability. The diagnosis of this inborn error of biogenic amine metabolism was accomplished by determining low concentrations of homovanillic, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenyl-ethyleneglycol in cerebrospinal fluid with normal biopterin metabolism and increased L-dopa, in plasma, cerebrospinal fluid, and urine. Greatly reduced activity of aromatic L-amino acid decarboxylase in plasma confirmed this diagnosis. Combined treatment with pyridoxine, tranylcypromine, and bromocriptine produced some clinical improvement.
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17 MeSH Terms