| Summary: | <p>Despite several proposed theories, the precise mechanism underlying acute oxygen sensing in type-1 cells of the carotid body remains elusive. This thesis investigates the role of Gq- coupled receptors and PLC signalling molecules in the regulation of carotid body type-1 cells by utilizing Ca2+ measurements and single channel electrophysiology. This thesis investigates the involvement of these signalling molecules in hypoxia-induced [Ca2+]i rise and TASK channel inhibition in type-1 cells. In addition, this thesis examines the role of PLC signalling molecules in mediating the effects of metabolic poisons and volatile anaesthetics on TASK channels in type-1 cells. This thesis seeks to address the question as to whether there might be a common signalling pathway mediating all these effects. Specifically, it proposes that lipid signalling may ultimately be central to all these forms of TASK channel regulation.</p>
<p>Following the general introduction and methods chapters, chapter 3 examines the effects of Gq- coupled receptors and PLC signalling molecules on the hypoxia-induced [Ca2+]i rise in type-1 cell. The results show that hypoxia-induced [Ca2+]i rise was sensitive to alterations in Gq-coupled receptors and PLC-signalling molecules, suggesting that these signalling molecules are involved in mediating the hypoxia-induced [Ca2+]i rise in type-1 cells.</p>
<p>Chapter 4, further examines the role of these signalling molecules by looking at their effects on the activity of TASK channels in type-1 cells. This chapter presents novel findings demonstrating the involvement of PLC signalling molecules in mediating the hypoxic inhibition of TASK channels in type 1 cells. It proposes a model for acute oxygen sensing in these cells, incorporating findings from chapters 3 and 4.</p>
<p>Chapter 5 examines the role of PLC signalling molecules in mediating the effects of metabolic inhibitors on TASK channels. Metabolic inhibitors are known to inhibit TASK channels in type-1 cells and other cell types. We further confirmed this and showed that these effects are not likely to be mediated by PLC-produced DAG.</p>
<p>Chapter 6 examines the interactions between DAG and halothane on TASK channels in type-1 cells. We demonstrated that DiC8, a DAG analogue, induced a strong, reversible, and dose-dependent inhibition of TASK channels and inhibited the halothane-induced activation of these channels. These novel findings support the hypothesis that anaesthetics and endogenous ligands may compete for binding sites in sensitive proteins.</p>
<p>In conclusion, this thesis presents novel findings on the role of Gq-coupled receptors and PLC signalling molecules in the regulation of carotid body type-1 cells and suggests that these signalling molecules are involved in mediating the responses of type-1 cells to various endogenous and exogenous stimuli. Additionally, it posits that PLC signalling molecules establish a connection between metabolic function and the modulation of TASK channels by hypoxia in type-1 cells.</p>
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