Yoshida, M; (2017) Role of BK channels in macrophage activation. Doctoral thesis , UCL (University College London).

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Abstract

The cells of the immune system expresses an array of different ion channels, yet their roles in these cells are not fully understood. The large-conductance voltage and calcium-activated potassium channel (BK channel) is a potassium ion channel, which is found in a wide variety of cells and tissues. Their biophysical properties and expression in excitable cells are extensively studied. However, their role in immune cells is unclear. In this thesis I have investigated the role of BK channels in macrophages. The expression of BK channels in the RAW264.7 mouse macrophages cell line was characterised by Western blot, immunofluorescence imaging and electrophysiological recordings. BK channels were predominantly associated with intracellular compartments in resting macrophages. Activation of RAW264.7 with ultrapure lipopolysaccharide (LPS) resulted in the upregulation of BK channel protein on the plasma membrane and the channel activity. To investigate the function of BK channels in these cells, both genetic and pharmacological approaches were used. These studies suggested that the role of the BK channel in macrophages is dependent on the sub-cellular location of the channel. Importantly this thesis suggests that plasma membrane located BK channels regulate the release of tumour necrosis factor- (TNF- and interleukin-6 receptor  (IL-6R from activated macrophages. IL-6 release was not affected. These results together suggested that a disintegrin and metalloprotease domain 17 (ADAM17) enzyme is negatively regulated by the plasma membrane BK channel. This thesis proposes a novel interaction between ion channels and the activity of a membrane metalloprotease. This project also identified the dynamic movement of BK channels during activation of macrophages. ADAM17 regulates the release of a diverse range of proteins including cytokines, growth factors, receptors and adhesion molecules, which are implicated in many fields including immunology, tissue regeneration, neurology and tumour growth. It is anticipated that this finding could stimulate further research.

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