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Title: Endocytosis and recycling of angiotensin II receptors
Author: Ball, S. L. R.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2003
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The main finding of this work is evidence that the AT1R is constitutively active and can undergo endocytosis and subsequent recycling in the absence of agonist. The application of a putative inverse agonist was able to increase the relative surface density in the presence of an inhibitor of novel protein synthesis. The internal pool partially colocalised with markers for early endosomes and the Golgi Apparatus, and was estimated to be 20% of the surface receptor density. This work has determined the presence of extracellular proteases that cleave the ang II into smaller peptide fragments within experimental assay timeframes. The putative cleavage product, ang III, was determined to induced AT1R endocytosis if present in sufficient concentrations. Simple mathematical models have been used to describe the changes in the surface receptor number in the presence of drugs, one of which is the Two-compartment model’. This model assumes that there are only two compartments in which the receptor can exist, the plasma membrane and inside the cell. It ignores trafficking time via endosomes to intracellular organelles such as sorting endosomes and lysosomes. A modified version of the two-compartment model was derived to include agonist depletion by internalisation or degradation and the effect of a basal level of constitutive internalisation. This work has determined that the internalisation profile of the AT1R can be fitted to the two-compartment model, although it is inadequate to describe the AT1R recycling profile and suggests that there is more than one internal receptor recycling pool. This work has also attempted to perform a detailed characterisation of an AT1R antagonist ZD 7155 in terms of receptor responses, and it effects upon ligand internalisation and receptor trafficking. It was concluded that insurmountable antagonism is a result of slow dissociation kinetics, but also may be due to residual antagonist during experimental procedures.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available