Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.573927
Title: The role of PICK1 and actin in AMPA receptor trafficking and synaptic plasticity
Author: Patton, Andrew Philip
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2012
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Abstract:
Protein Interacting with C Kinase (PICK1) plays an important role in the trafficking of AMPA receptors in response to cellular signals, a process that underlies synaptic plasticity, both long-term potentiation (LTP) and long-term depression (LTD). PICK1 interacts with many proteins, including an inhibitory interaction with Actin-Related Proteins 2/3 (Arp2/3) at tryptophan 413 in PICK1. Recently, a putative phosphorylation site on PICK! adjacent to the Arp2/3 interaction site at serine 412 has been identified. I have assessed the functional implications of the link to Arp2/3 and its adjacent phosphorylation site using the PICK1 mutants, W413APICK1 (Arp2/3 non-interacting) along with S412APICK1 and S412DPICK1 (phosphonull and phosphomimetic mutants respectively). Two slice culture approaches were used to study the effects of these mutants. Semi-acute overnight-cultured slices were injected with recombinant Sindbis virus at the CA1 pyramidal cell layer to overexpress EGFP or EGFP along with WTPICK1 or W413APICKl. Longer-term organotypic hippocampal slices were biolistically transfected to overexpress EGFP with WTPICK1, S412APICK1 or S412DPICK1. Electrophysiological recordings made from fluorescent CA1 pyramidal cells were used to investigate the role PICK1 and its association with the Arp2/3 complex play in LTD. Under basal conditions, overexpression of WTPICK1 caused an internalisation of GluA2-containing receptors that occludes LTD. In contrast, when W413APICK1 or S412APICK1 was overexpressed, both basal trafficking and LTD were blocked. Finally, LTD is absent in S412DPICK1-overexpressing slices, although it is unclear whether this is through a block or an occlusion mechanism. These results show that the interaction between PICK1 and Arp2/3 is essential for the internalisation of GluA2-containing AMPARs in the hippocampus during LTD. Furthermore, it appears that this interaction is controlled by a phosphorylation site on PICK1 that also plays an important role in AMPAR trafficking during LTD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.573927  DOI: Not available
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