Browsing by Author "Thompson, Roger J"

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    Pannexin 1 Channels as a Therapeutic Target: Structure, Inhibition, and Outlook
    (2020-01) Navis, Kathleen E; Fan, Churmy Y; Trang, Tuan; Thompson, Roger J; Derksen, Darren J
    Pannexin 1 (Panx1) channels are transmembrane proteins that release adenosine triphosphate and play an important role in intercellular communication. They are widely expressed in somatic and nervous system tissues, and their activity has been associated with many pathologies such as stroke, epilepsy, inflammation, and chronic pain. While there are a variety of small molecules known to inhibit Panx1, currently little is known about the mechanism of channel inhibition, and there is a dearth of sufficiently potent and selective drugs targeting Panx1. Herein we provide a review of the current literature on Panx1 structural biology and known pharmacological agents that will help provide a basis for rational development of Panx1 chemical modulators.
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    Spinal Oxygen Sensors: location, function and mechanism
    (2021-04-05) Orsi Barioni, Nicole; Wilson, Richard JA.; Whelan, Patrick.; Zocal, Daniel B; Ousman, Shalina S; Thompson, Roger J; Gordon, Grant RJ.
    In hypoxic conditions, the mammalian body composes cardiorespiratory responses aimed to increase oxygen supply to vital organs. Although the carotid bodies are the primary oxygen chemoreceptors for breathing, data in the literature show that hypoxia-triggered cardiovascular responses remain in their absence, suggesting the existence of an additional hypoxia sensor responsible to elicit those responses. In the present work, my objectives were to determine 1) the origin of the cardiovascular responses to hypoxia in the absence of the carotid bodies; 2) the function of these oxygen sensors in rescuing cardiorespiratory control under hypoxia; and 3) the oxygen sensing mechanism through which these cells compose the hypoxic response. Using in vivo, in situ, en bloc and patch clamp preparations combined with pharmacological, immunological and genetic approaches, our data show that thoracic spinal preganglionic neurons (SPNs) are highly oxygen sensitive and this sensitivity is not mediated by surrounding glia (although spinal glia also seem to be oxygen sensitive). Additionally, these spinal oxygen sensors (SOS) are not only capable of increasing phrenic activity independent of the brainstem, but also modulating the brainstem’s process of gasp generation under asphyxia by increasing sympathetic output and promoting autoresuscitation – in some cases producing gasps on its own. Furthermore, our results suggest that the SOS are equipped with a novel oxygen sensing mechanism involving neuronal nitric oxide synthase (NOS1), expressed abundantly in SPNs. The high expression levels of NOS1 in SPNs causes high levels of NADPH consumption. However, as oxygenation decays in hypoxia, NOS1 becomes dormant due to its high KmO2, making NADPH available for NOX2 in the production of ROS. The increased ROS concentration inside the SPNs triggers TRP channels and IP3R, culminating in elevated intracellular calcium and, consequently, neuronal depolarization. In conclusion, the present thesis investigates a spinal oxygen sensor which potentially contributes to survival behaviours and appears to use a novel oxygen sensing mechanism.