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Regulation of extracellular signal-regulated protein kinases (ERK) 1 and 2 in synaptic nerve terminals

Lee, Vivian Wing Yan; (2006) Regulation of extracellular signal-regulated protein kinases (ERK) 1 and 2 in synaptic nerve terminals. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Activation of extracellular signal-regulated kinases 1 and 2 (ERK 1 and 2) is a key signalling event in the modulation of presynaptic function. This study looks at the upstream regulation of ERK 1 and 2 signalling in rat cerebrocortical synaptosomes. Kinase activation assays based on phospho-state specific antibodies revealed two major inputs for the activation of ERK 1 and 2: i) a neurotrophin-mediated signalling to ERK 1 and 2 which is dependent on the activation of small GTP-binding protein Ras and the presence of Ca ii) a Ca -dependent activation of ERK 1 and 2, stimulated by depolarisation or by the Ca ionophore ionomycin. Treatment of synaptosomes with Ca2+ chelators showed that basal ERK 1 and 2 activation was partly supported by Ca2+ from intracellular sources, whilst depolarisation-dependent activation of ERK 1 and 2 was entirely attributable to extracellular Ca influx. Like the BDNF-mediated activation, this Ca -dependent signalling to ERK was contingent on Ras, as evinced by the use of Ras inhibitor lovastatin. Using inhibitors of Ca /CaM-dependent protein kinase II (CaMKII) and phosphatidylinositol-3-kinase (PI3K), we next showed that both kinases are involved in mediating the Ca -dependent ERK 1&2 pathway. Furthermore, the Src family kinase (SFK) inhibitor, PP2, strongly reduced Ca -dependent ERK 1 and 2 activation, suggesting a role for non-receptor tyrosine kinases (nRTKs) in upstream signalling. Finally, using okadaic acid, roscovitine and baclofen respectively, we showed that the duration and efficacy of ERK 1 and 2 activation are determined by the function of protein phosphatase 2A (PP2A), cyclin- dependent kinase 5 (cdk5) and the presynaptic Gj/0-coupled GABAb receptors. Interestingly, our data demonstrate that baclofen-mediated inhibition of ERK 1&2 can be overridden by BDNF stimulation, revealing a potential feedback and cross-talk mechanism between the excitatory ERK and inhibitory GABA cascades. Together, these studies elucidate the role of ERK 1 and 2 as a hub for signalling in the nerve terminal.

Type: Thesis (Doctoral)
Title: Regulation of extracellular signal-regulated protein kinases (ERK) 1 and 2 in synaptic nerve terminals
Identifier: PQ ETD:594401
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1446422
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