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Permanent link (DOI): https://doi.org/10.7939/R30P0X24R

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Regulation of Ca2+ signals in rat carotid glomus cells Open Access

Descriptions

Other title
Subject/Keyword
electrophysiology
glomus cell
carotid body
Ca2+ imaging
reactive oxygen species
antioxidant
bicarbonate
exocytosis
Ca2+ homeostasis
mitochondria
Ca2+ clearance
hypoxia
mitochondrial uniporter
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Yan, Lei
Supervisor and department
Tse, Frederick (Centre for Neuroscience and Department of Pharmacology)
Tse, Amy (Centre for Neuroscience and Department of Pharmacology)
Examining committee member and department
Syed, Naweed (Department of Cell Biology & Anatomy)
Baker, Glen (Centre for Neuroscience and Department of Psychiatry)
Ali, Declan (Centre for Neuroscience and Department of Biological Sciences)
Ballanyi, Klaus (Centre for Neuroscience, Department of Physiology and Department of Pediatrics)
Department
Centre for Neuroscience
Specialization

Date accepted
2013-07-03T11:47:13Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Glomus cells of the carotid body are peripheral chemoreceptors that detect changes in arterial oxygen levels. Hypoxia suppresses oxygen-sensitive K+ channels in glomus cells, resulting in cytosolic [Ca2+] ([Ca2+]i) elevation in glomus cells via the activation of voltage-gated Ca2+ channels. The resultant transmitter release stimulates the carotid sinus nerve (CSN) and the triggering of respiratory and cardiovascular reflexes. Hypoxia also causes mitochondrial depolarization and mitochondrial inhibitors have been shown to cause depolarization in glomus cells via the inhibition of oxygen-sensitive K+ channels. In the first project, with the patch clamp technique in conjunction with [Ca2+]i measurement (with indo-1), I found that mitochondrial Ca2+ uptake played a dominant role in cytosolic Ca2+ clearance in rat glomus cells. Importantly, mitochondrial inhibition increased the duration of the Ca2+ signal triggered by a voltage-clamped depolarization, which contributed to an enhancement of exocytotic response. Under hypoxic conditions, there was a slowing in cytosolic Ca2+ clearance, consistent with the scenario that hypoxia caused mitochondrial depolarization and thus reduced mitochondrial Ca2+ uptake. It has been reported that the hypoxia-triggered CSN discharge is enhanced in the presence of extracellular bicarbonate ion (HCO3-). Therefore, in the second project, I investigated the role of HCO3- in the regulation of Ca2+ dynamics in glomus cells. Extracellular HCO3- slowed the rate of cytosolic Ca2+ clearance in a concentration-dependent manner. Measurement of the mitochondrial Ca2+ signal with rhod-2 shows that HCO3- reduced mitochondrial Ca2+ uptake and this inhibition was abolished in cells treated with scavengers of reactive oxygen species (ROS). Thus, HCO3- reduced mitochondrial Ca2+ uptake via a mechanism that was dependent on ROS. Overall, my results show that mitochondrial Ca2+ uptake in glomus cells could be reduced by hypoxia or by the presence of a physiological concentration of extracellular HCO3-. This effect resulted in a slowing in cytosolic Ca2+ clearance and more transmitter release. The multiplicity of the influences of mitochondria on glomus cell Ca2+ signaling and exocytosis underscores the importance of mitochondria in hypoxic chemotransduction in the carotid bodies.
Language
English
DOI
doi:10.7939/R30P0X24R
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Lei Yan, Andy K. Lee, Frederick W. Tse, Amy Tse. (2012).  http://www.sciencedirect.com/science/article/pii/S0143416011002326

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