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Title: Structure/function analysis and hypoxic regulation of STREX variant BK channels
Author: Saleem, F.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2008
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Hypoxia sensitivity of STREX has previously been shown to be dependent upon a cysteine motif (-CSC-) in the STREX insert that is also within a putative phosphorylation motif. This thesis thus had three main aims: 1) to develop a high throughput assay to allow discrimination of different BK channel splice variants and their modulation 2) to characterise the role of cysteine residues within the STREX exon that may determine hypoxia sensitivity of the channel, and finally 3) to examine the modulation of the hypoxia response by intracellular ATP. During the course of these experiments the monovalent ion lithium (Li+) was observed to robustly block the STREX response to hypoxia. Li+ shares physiochemical properties with the divalent magnesium (Mg2+) ion hence the role of Mg2+ in the STREX hypoxia response was also investigated. Mg2+ modulated the response in a similar fashion to ATP. In addition it was seen that Li+ and Mg2+ decreased the single channel conductance of STREX and ZERO variants, Mg2+ also increased STREX channel open probability. However, while Li+ and Mg2+ may share similar mechanisms/sites to modulate channel conductance the differential effect of Li+ and Mg2+ on the hypoxia response suggest Li+ acts via a site/mechanism distinct from that of Mg2+. Taken together, these data suggest that alternative pre-mRNA splicing is an important determinant of BK channel pharmacology and that cysteine and other residues within the STREX insert play a key role in function of the channel and its response to hypoxia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available