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.

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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.