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Title: The role of specific receptor domains in signal transduction by the VIP2 receptor
Author: MacKenzie, Christopher J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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Receptors for the neuropeptides VIP and PACAP belong to a novel sub-family of G protein-coupled receptors, the secretin/calcitonin/parathyroid hormone receptor family. The rat VIP2 receptor was recently cloned in this laboratory and the present project was carried out to characterise the signalling mechanisms used by this receptor and define the role of crucial receptor domains. These studies have primarily involved the transient expression of receptors in host cells. The results demonstrated for the first time that both the VIP1 and VIP2 receptors can stimulate phospholipase C (PLC) in addition to adenylyl cyclase (AC) and that this PLC stimulation occurs by a pertussis toxin(PTx)-sensitive mechanism. Corresponding GTPγS modulation of ligand-binding to the VIP2 receptor in COS7 cell membranes was shown to be partially PTx-sensitive, suggesting an interaction of the receptor with a PTx-sensitive G protein. An epitope-tagged human VIP2 receptor was expressed in COS7 cells and immunoprecipitated with its associated G proteins for Western-blotting studies. Immunoreactivity for Gαq, Gαs and a member of the Gαi/o/t/z family, other than Gαi1 or Gαi2, appeared to be associated with the receptor. The use of specific calcium channel blockers identified a role for receptor-mediated calcium influx in VIP2 receptor-mediated PLC stimulation. The PACAP and VIP2 receptors contain many common structural features but have their own distinct pharmacological profiles. The function of specific domains of the VIP2 receptor was investigated by creating PACAP/VIP2 receptor chimaeric constructs and C-terminal truncations of the VIP2 receptor. These constructs allowed identification of the primary region of the receptor responsible for ligand-binding and the probable site of interaction with a PTx-sensitive G protein and also assessment of any contribution of the C-terminus to AC and PLC stimulation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available