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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. Wheatley, Mark Colleges (2008 onwards) > College of Life & Environmental Sciences School of Biosciences QH301 Biology University of Birmingham 4019
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