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Title: Regulation of Mitogen-activated protein kinases by Group I metabotropic glutamate receptors
Authors: Thandi, Sukhwinder
Award date: 2004
Presented at: University of Leicester
Abstract: The regulation of mitogen-activated protein kinase (MAPK) activities by the group I metabotropic glutamate (mGlu) receptors, mGlu1a and mGlu5a, has been studied in Chinese hamster ovary (CHO) cells, where receptor expression is under inducible control. Both mGlu receptors stimulated comparable, robust and transient increases in the activity of the extracellular signal-regulated kinase (ERK) subgroup. Further, the mGlu1a, but not the mGlu5a receptor was found to mediate an increase in the activity of c-Jun N-terminal kinase (JNK). Examination of the signalling profile of mGlu1/mGlu5a receptor-mediated ERK activation revealed clear differences in the G-protein subpopulations involved, with only mGlu1a receptor-mediated ERK responses attenuated by pertussis toxin (PTx) pre-treatment. Both mGlu1a and mGlu5a receptor-mediated ERK activation occurred via mechanisms dependent on the non-receptor tyrosine kinase, Src, but independent of phosphoinositide 3-kinase activity, PKC and intracellular and/or extracellular Ca2+ concentration. Data also demonstrate a requirement for PDGF receptor tyrosine kinase activity in ERK activation by the mGlu1a, but not the mGlu4a receptor. The mGlu1a receptor-mediated JNK response, unlike ERK activation by the same receptor, was insensitive to PTx pre-treatment and occurred via mechanisms independent of intracellular and/or extracellular Ca2+ concentration, Src kinase and was unaffected by PKC down-regulation. The delayed onset of JNK activation by the mGlu1a receptor was not found to be a result of earlier ERK activation. Stimulations of mGlu1a/mGlu5a receptors, did not alter cellular proliferation, as measured by DNA synthesis, or have a marked effect on cytoskeletal organisation, as measured by immunocytochemistry, indicating that the activation of mitogenic signalling by these two mGlu receptors does not result in changes in growth in these cells. These studies highlight important differences in the activation and signalling pathways utilised to regulate MAP kinases.
Type: Thesis
Level: Doctoral
Qualification: PhD
Rights: Copyright © the author. All rights reserved.
Appears in Collections:Theses, Dept. of Cell Physiology and Pharmacology
Leicester Theses

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