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A kinetic study of receptor activation of the G-protein gated K+ channel

Benians, Amy; (2003) A kinetic study of receptor activation of the G-protein gated K+ channel. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The cloned G-protein gated inwardly rectifying K+ channel (a tetramer composed of Kir3.1-3.4 subunits) is activated by direct binding of Gβγ dimers, liberated by receptor activation of the Gi/o subfamily of heterotrimeric guanine nucleotide binding (G)-proteins. The interaction of these three membrane-associated components, G-protein coupled receptor (GPCR), heterotrimeric G-protein and channel, is rapid in native cells, with full channel activation via the GABA-B receptor occurring within a few hundred milliseconds (Sodickson & Bean, 1996 and 1998), and current deactivation occurring with a time constant of 1-2 seconds. Recent discovery of the Regulators of G-protein signalling (RGS) protein family has solved a major discrepancy between the slow deactivation of purified G-proteins and the fast deactivation of G-protein mediated signalling pathways. Their discovery has generated considerable interest in the kinetics of G-protein signalling and the organisation of these signalling components in the cell membrane. For these studies, the GIRK signalling system was reconstituted in mammalian HEK-293 cell lines, stably expressing the cloned neuronal channel subunits (Kir3.1 and Kir3.2A) plus a Gi/o-coupled GPCR (α2A adrenergic, A1 adenosine, D2 dopamine, M4 muscarinic and the heterodimeric GABA-B1b/2 receptors). Chapter 1 provides a general introduction to G-protein signalling and reviews our current understanding of the factors involved in the regulation of GERK channels. In Chapter 2, the methods and experimental protocols used in the study are described. In Chapter 3, I present a systematic analysis of the factors that contribute to the rapid activation of the channel complex, and in Chapter 4 the characteristic fast desensitisation of receptor-activated currents is examined. Factors influencing channel deactivation upon removal of agonist are explored in Chapter 5, and in Chapter 6 I describe the effects of the novel RGS protein family in these cell lines. Conclusions and future directions for this work are presented in Chapter 7.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: A kinetic study of receptor activation of the G-protein gated K+ channel
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Potassium channels
URI: https://discovery.ucl.ac.uk/id/eprint/10107293
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