Browsing by Subject "Protein Biosynthesis"
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Item Multiple Gq-Coupled Receptors Converge on a Common Protein Synthesis-Dependent Long Term Depression that is Affected in Fragile X Syndrome(2007-12-18) Volk, Lenora Joanne; Huber, KimActivation of Gq-coupled group I metabotropic glutamate receptors (mGluR1, mGluR5) induces long-term synaptic depression (LTD) that requires rapid, dendritic protein synthesis. The significance of protein synthesis-dependent mGluR LTD to cognitive function is highlighted by the recent finding that mGluR-dependent LTD is enhanced and protein synthesis-independent in the mouse model of fragile X syndrome mental retardation (FXS, Fmr1 KO mice). In fact, group I mGluR antagonism ameliorates some symptoms of FXS in model organisms. However, disagreement exists in the literature as to the specific roles of mGluR1 and mGluR5 in LTD. Using pharmacological and genetic manipulations, I find that mGluR1 or mGluR5 activation is sufficient to induce LTD. In contrast, I see a selective role for persistent mGluR1 activity in expression of LTD induced with the group I mGluR agonist, DHPG. These data demonstrate a novel role for mGluR1 in induction and expression of LTD at hippocampal Schaffer collateral-CA1 synapses and confirm a role for mGluR5 in induction of LTD at this synapse. LTD induced synaptically with paired-pulse low frequency stimulation (PP-LFS) is Gq- and protein synthesis-dependent and shares common signaling and expression mechanisms with DHPG-induced LTD. However, I find that PP-LFS LTD persists in the presence of group 1 mGluR antagonists and in mGluR1 or mGluR5 knockout mice. These data led to the hypothesis that Gq-coupled receptors other than mGluRs are activated by PP-LFS to induce LTD, and LTD mediated by these receptors should share similar signaling and expression mechanisms with mGluR LTD. A previous study shows that muscarinic acetylcholine receptors (mAChRs) activate protein synthesis in hippocampal CA1 dendrites. Data presented here demonstrate that PP-LFS activates both Gq-coupled mAChRs and mGluRs to induce LTD. Pharmacological activation of mAChRs induces LTD that requires rapid protein synthesis and activation of ERK and mTOR translational activation pathways. New proteins maintain mAChR-dependent LTD through a persistent decrease in surface AMPA receptors. In addition, mAChR LTD is enhanced and protein synthesis-independent in Fmr1 knock-out mice. These data reveal that multiple Gq-coupled receptors converge on a common protein synthesis-dependent LTD mechanism that is aberrant in FXS. These findings suggest novel therapeutic strategies for FXS in the form of mAChR antagonists.Item Regulation of Liver Metabolism by Fibroblast Growth Factor 19(2012-07-20) Kir, Serkan; Mangelsdorf, David J.Fibroblast Growth Factor (FGF) 19 is a postprandial enterokine up-regulated by bile acid receptor FXR upon bile acid uptake into the ileum. FGF19 inhibits hepatic bile acid synthesis through transcriptional repression of cholesterol 7 alpha-hydroxylase (CYP7A1) via a mechanism involving nuclear receptor Small Heterodimer Partner (SHP). Here, I show that two other nuclear receptors, Hepatocyte Nuclear Factor 4 alpha (HNF4 alpha) and Liver Receptor Homolog-1 (LRH-1), enable SHP binding to the Cyp7a1 promoter and therefore are important for negative feedback regulation of Cyp7a1. HNF4 alpha and LRH-1 are also crucial activators of Cyp7a1 transcription. They maintain active transcription histone marks on the Cyp7a1 promoter, whereas FGF19 down-regulates these marks in a SHP-dependent way. Secondly, I show that the MEK/ERK signaling pathway is an integral regulator of bile acid metabolism. ERK activity is necessary to maintain hepatic Shp and Cyp7a1 transcription at their physiologic levels. Inhibition of this pathway causes loss of Shp transcription by disrupting HNF4 alpha and LRH-1 binding to the Shp promoter. Independent from the effects on Shp, MEK/ERK inhibition induces Cyp7a1 transcription. Unexpectedly, the MEK/ERK pathway is not required for repression of Cyp7a1 by FGF19. Although this pathway is activated by FGF19 in livers of Fgf receptor 4 (Fgfr4)-deficient mice probably via other FGFRs, Cyp7a1 repression is largely impaired. Thus, I propose that a signaling mechanism uniquely regulated by FGFR4 must be responsible for FGF19-dependent repression of bile acid synthesis. In addition to its roles in bile acid metabolism, I also show that FGF19 stimulates hepatic protein and glycogen synthesis, but does not induce lipogenesis. The effects of FGF19 are independent of the activity of either insulin or the protein kinase Akt, and instead are mediated through a mitogen-activated protein kinase signaling pathway that activates components of the protein translation machinery and stimulates glycogen synthase activity. Mice lacking FGF15 (the mouse FGF19 ortholog) fail to properly regulate blood glucose and fail to maintain normal postprandial amounts of liver glycogen. FGF19 treatment restored the loss of glycogen in diabetic animals lacking insulin. Thus, FGF19 activates a physiologically important, insulin-independent endocrine pathway that regulates hepatic protein and glycogen metabolism. [Keywords: bile acids, FGF19, CYP7A1, HNF4 alpha, LRH-1, SHP, protein synthesis, glycogen synthesis, ERK, GSK3]