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Title: Regulation of the thiazide-sensitive sodium chloride transporter, NCCT
Author: Glover, M.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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The thiazide-sensitive sodium chloride transporter, NCCT is found in the distal convoluted tubule. Reduced NCCT activity caused by thiazide diuretics or Gitelman syndrome leads to salt wasting and reduced blood pressure. Conversely, excessive NCCT activity seen in Gordon syndrome, due to mutations in one of two regulatory kinases of the With No Lysine (WNK) kinase family, WNK1 and WNK4, results in hypertension. Regulation of NCCT is increasingly acknowledged to involve a scaffold of proteins composed of several kinases including WNK1, WNK4, the third member of the WNK kinase family, WNK3 and the phylogenetically related SPAK and OSR1 kinases. The molecular details of this regulatory pathway have however only recently begun to emerge and are only partially characterized. This thesis attempts to addresses the regulation of NCCT by several members of this regulatory scaffold. The Xenopus oocyte expression system was used to investigate the role of WNK4, alternative isoforms of WNK3, protein phosphatases and SPAK in regulating NCCT in vitro. The importance of phosphorylation of a key N terminal Threonine in NCCT emerged from these studies as well as highlighting key domains within WNK3 capable of altering the direction of NCCT regulation and suggesting a counter-regulatory role for protein phosphatase 4. The phenotype of a SPAK kinase-dead knock-in mouse was characterised. These mice shared several features of Gitelman syndrome or therapy with thiazide diuretics; specifically salt sensitive hypotension, hypomagnesaemia and hypokalaemia. This suggests that SPAK may be a key regulator of blood pressure in vivo and perhaps a novel antihypertensive drug target.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available