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Title: A crucial role of a shared extracellular loop in apamin sensitivity and maintenance of pore shape of KCa2 channels
Author: Weatherall, Kate L.
ISNI:       0000 0004 2725 2160
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2011
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Activation of small conductance calcium (Ca2+)-activated potassium (Kca2) channels regulates membrane excitability. The cloning of the Kca2 channel family revealed three closely related members KCa2.1-2.3 that are widely distributed, with partially overlapping, but clearly distinct distribution patterns in the CNS, smooth muscle and heart. It is difficult to discern the physiological role of individual channel subtypes as most inhibitors or enhancers do not discriminate between subtypes and it is likely that channels can form heteromeric complexes of different subtypes. The archetypical inhibitor apamin displays some selectivity between Kca2 channel subtypes, with KCa2.2 being the most sensitive, followed by Kca2.3 and then Kca2.1. Sensitivity of Kca2.1 is species-specific, with the human isoform being blocked by the toxin while the rat is insensitive. The sensitivity of the mouse isoform is unknown. A combination of mutagenesis and electrophysiology were used to determine the residues within Kca2 channels that comprise the binding site or attribute to the mechanism of apamin block. The study focuses on the extracellular loop region between the third and fourth transmembrane domains which has been shown to interact with the toxin. A three amino acid motif within this loop was identified which is essential for apamin activity and regulates the shape of the channel pore. The S3-S4 loop of one subunit was also shown to overlap the outer pore of the adjacent subunit, with apamin interacting with both regions. This provides a unique binding site for each combination of Kca2 subunits within a eo-assembled channel that can be targeted to produce inhibitors specific for heteromeric Kca2 channels.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available