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A mutagenic approach to elucidating aquaporin function

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Kitchen, Philip (2016) A mutagenic approach to elucidating aquaporin function. PhD thesis, University of Warwick.

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Abstract

Aquaporins (AQPs) are transmembrane proteins that facilitate the movement of water molecules across biological membrane by osmosis.

Green fluorescent protein-tagged aquaporin 4 relocalized to the plasma membrane of HEK293 cells in response to reduced tonicity and this phenomenon was reproduced for endogenous AQP4 in primary astrocyte cultures. The mechanism was dependent on phosphorylation at serine-276 by PKA and required activation of CaM. AQP4 knockout animals are protected from brain edema so pharmacologically modulating the subcellular localization of AQP4 may provide a platform for an alternative or complementary approach to hyperosmotic solution based edema therapies. Using the same methodology, we also describe some of the factors controlling AQP5 plasma membrane abundance.

AQPs have a signature aromatic/arginine (ar/R) motif that is thought to aid in solute selectivity. Mutants of AQP4 in this region permitted the passage of small solutes differently to AQP1, questioning the validity of a generalized model of AQP solute exclusion. Furthermore, the relative selectivity for glycerol and urea of AQPs could be modulated independently of the physical size of the Ar/R region, suggesting that lack of solute exclusion and solute selectivity are not the same thing.

AQPs retain homotetrameric quaternary structures, but the structural basis and functional relevance of this assembly is not known. Mutants of an intracellular loop of AQP4 had reduced ability to form tetramers and, despite no change in constitutive levels of membrane localization or water permeability, had reduced capacity to relocalize in response to hypotonicity.

Item Type: Thesis (PhD)
Subjects: Q Science > QP Physiology
Library of Congress Subject Headings (LCSH): Aquaporins, Mutagenesis
Official Date: 2016
Dates:
DateEvent
2016Submitted
Institution: University of Warwick
Theses Department: Molecular Organisation and Assembly in Cells
Thesis Type: PhD
Publication Status: Unpublished
Extent: 218 leaves
Language: eng

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