Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transgenic and knockout mice are used extensively to elucidate the molecular mechanisms of hippocampal synaptic plasticity. However, genetic and phenotypic variations between inbred mouse strains that are used to construct genetic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recording methods, we compared the membrane biophysical, cellular electrophysiological, and synaptoplastic properties of hippocampal CA1 neurons in four specific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hippocampal long-term potentiation (LTP) induced by theta-pattern stimulation, and by repeated multi-burst 100-Hz stimulation at various interburst intervals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenance of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was significantly enhanced in129/SvEms slices, but not in DBA and CBA slices. Long-term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons showed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synaptically-evoked glutamatergic postsynaptic currents did not significantly differ among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduced hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitation induced by forskolin (an activator of adenylate cyclase) and IBMX (a phosphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic facilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not in BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic facilitation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some inbred mouse strains may be "tuned" to particular temporal patterns of synaptic activity. From a broader perspective, our data support the notion that strain-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use genetically modified mice to explore the molecular bases of synaptic plasticity.
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PMID:Differential maintenance and frequency-dependent tuning of LTP at hippocampal synapses of specific strains of inbred mice. 1106 91

Ribosomal biogenesis involves the processing of pre-ribosomal RNA. A deficiency of some ribosomal proteins (RPs) impairs processing and causes Diamond Blackfan anemia (DBA), which is associated with anemia, congenital malformations and cancer. p53 mediates many features of DBA, but the mechanism of p53 activation remains unclear. Another hallmark of DBA is the upregulation of adenosine deaminase (ADA), indicating changes in nucleotide metabolism. In RP-deficient zebrafish, we found activation of both nucleotide catabolism and biosynthesis, which is consistent with the need to break and replace the faulty ribosomal RNA. We also found upregulation of deoxynucleotide triphosphate (dNTP) synthesis - a typical response to replication stress and DNA damage. Both RP-deficient zebrafish and human hematopoietic cells showed activation of the ATR/ATM-CHK1/CHK2/p53 pathway. Other features of RP deficiency included an imbalanced dNTP pool, ATP depletion and AMPK activation. Replication stress and DNA damage in cultured cells in non-DBA models can be decreased by exogenous nucleosides. Therefore, we treated RP-deficient zebrafish embryos with exogenous nucleosides and observed decreased activation of p53 and AMPK, reduced apoptosis, and rescue of hematopoiesis. Our data suggest that the DNA damage response contributes to p53 activation in cellular and zebrafish models of DBA. Furthermore, the rescue of RP-deficient zebrafish with exogenous nucleosides suggests that nucleoside supplements could be beneficial in the treatment of DBA.
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PMID:The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia. 2481 35

Ribosome biogenesis plays key roles in cell growth by providing increased capacity for protein synthesis. It requires coordinated production of ribosomal proteins (RP) and ribosomal RNA (rRNA), including the processing of the latter. Here, we show that, the depletion of RPS19 causes a reduction of rRNA synthesis in cell lines of both erythroid and non-erythroid origin. A similar effect is observed upon depletion of RPS6 or RPL11. The deficiency of RPS19 does not alter the stability of rRNA, but instead leads to an inhibition of RNA Polymerase I (Pol I) activity. In fact, results of nuclear run-on assays and ChIP experiments show that association of Pol I with the rRNA gene is reduced in RPS19-depleted cells. The phosphorylation of three known regulators of Pol I, CDK2, AKT and AMPK, is altered during ribosomal stress and could be involved in the observed downregulation. Finally, RNA from patients with Diamond Blackfan Anemia (DBA), shows, on average, a lower level of 47S precursor. This indicates that inhibition of rRNA synthesis could be one of the molecular alterations at the basis of DBA.
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PMID:Depletion of ribosomal protein S19 causes a reduction of rRNA synthesis. 2773 13