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

Logan, Richard Thomas (2013). The structure and function of the vasopressin V\(_1\)\(_a\) receptor. University of Birmingham. Ph.D.

Preview

Logan13PhD.pdf
PDF - Accepted Version
Download (2MB)

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:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):