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Title: The structure and function of the human vasopressin receptors
Author: Bailey, Sian
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2017
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The human vasopressin receptors (V1aR, V1bR and V2R) are G-protein-coupled receptors (GPCR) and mediate the effects of [Arg8]vasopressin (AVP). The influence of G-protein selectivity on ligand binding was probed by exchanging G-protein selectivity of the V1aR and V2R. This was achieved by generating a V1aR chimera that was capable of coupling to Gs and a V2R chimera that signalled via Gq/11. A conserved Ar1-X-Ar2 motif in ECL 1 of Family A GPCRs was identified. The vasopressin receptors lack the second aromatic residue, however tryptophan (Trp2·64) is conserved at the beginning of ECL 1. Removal of the Trp2·64 sidechain in the V1aR resulted in loss of high affinity AVP binding. Transfer of tryptophan, to recreate the Ar1-X-Ar2 motif, did not recover high affinity AVP binding. Pharmacological chaperones are non-peptide ligands that can selectively rescue intracellularly retained receptors. As demonstrated herein, pharmacological chaperones are also useful laboratory tools for investigating low-expressing mutant receptors. Additionally, mutagenesis was utilised to investigate the chaperone capability of sub-type selective ligands by increasing the affinity of the ligand for the 'wrong' receptor subtype. A potential three-way interaction between the V1bR, CRFR1 and RAMP2 was probed. The study also investigated the effects of RAMP2 on two CRFR1 isoforms.
Supervisor: Not available Sponsor: Biotechnology and Biological Sciences Research Council Midlands Integrative Biosciences Training Partnership (BBSRC MIBTP)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QR Microbiology