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The structure and function of the vasopressin V\(_1\)\(_a\) receptor

Logan, Richard Thomas (2013)
Ph.D. thesis, University of Birmingham.

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Abstract

The neurohypophysial hormone [arginine\(^8\)]vasopressin (AVP) exerts the majority of its physiological roles through the G-protein-coupled receptor, V\(_1\)\(_a\) R. AVP binding to the V\(_1\)\(_a\) R promotes receptor activation and generates signalling though the inositol phosphate pathway.

ICL 2 has been implicated in many aspects of GPCR signalling and crystallographic data highlight the structurally dynamic nature of this region. A complete alanine-scanning study of ICL 2 has not previously been conducted in a GPCR but is presented here in the prototypical peptide-ligand GPCR, V\(_1\)\(_a\) R. However, a role of Leu\(^3\)\(^.\)\(^5\)\(^8\) in mediating G-protein-dependent signalling was observed in the V\(_1\)\(_a\) R – a finding that has previously been reported in other GPCRs.

Upon agonist binding, the structural rearrangements of TM V and TM VI are integral in signal transduction in GPCRs. Two highly conserved residues, Tyr\(^5\)\(^.\)\(^5\)\(^8\) and Ile\(^6\)\(^.\)\(^4\)\(^0\) are key players in the activation process. Given their high conservation, it was presumed that their roles are universal throughout the rhodopsin-like GPCR family. The systematic substitution of these two residues in the V\(_1\)\(_a\) R demonstrate the receptor-specific nature of substitutions of Tyr\(^5\)\(^.\)\(^5\)\(^8\) and Ile\(^6\)\(^.\)\(^4\)\(^0\) given that findings in the V\(_1\)\(_a\) R are not recapitulated in the generally limited mutagenic studies in other receptors.

Type of Work:Ph.D. thesis.
Supervisor(s):Wheatley, Mark
School/Faculty:Colleges (2008 onwards) > College of Life & Environmental Sciences
Department:School of Biosciences
Subjects:QH301 Biology
Institution:University of Birmingham
ID Code:4019
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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