Chemoreceptor cells in the carotid body (CB cells), in response to hypoxia, initiate homeostatic mechanisms to regulate breathing and autonomic nerve system activity. A widely accepted model for O2 sensing by CB cells is that hypoxia inhibits K+ current and thereby causes depolarization, opening of voltage-dependent Ca2+ channels, and elevation of [Ca2+]i. Upon rise of [Ca2+]i, CB cells secrete transmitters that act on sensory nerve terminals to elicit action potentials that reach the brainstem cardio-respiratory centers. In CB cells, hypoxia is believed to target a number of K+ channels to cause excitation. One of the K+ channels inhibited by hypoxia is TASK (TASK-1 and TASK-3) that is highly expressed in CB cells and active across the physiological range of Em. The mechanism of inhibition of TASK by hypoxia is not yet known. Recently, we discovered a Na+ permeable channel that is activated by hypoxia (hypoxia-activated or HA channel) in rat CB cells. Therefore, we hypothesize that inhibition of K+ current and activation of Na+ current both contribute to hypoxia-induced depolarization of CB cells. Recent studies suggest that hydrogen sulfide (H2S) is generated during hypoxia and mediates the hypoxia-induced increase in carotid sinus nerve activity and ventilation. However, the role of H2S in hypoxia-induced excitation of CB cells remains undefined. Therefore, we propose three specific aims to identify the mechanisms of hypoxia-induced modulation of TASK and the HA channel, and the role of the HA channel in hypoxia-induced excitation in CB cells.
Aim 1 tests the hypothesis that hypoxia inhibits TASK via generation of H2S, and investigates the mechanism of this inhibition. The role of hemeoxygenase-2 in this process is also studied, as carbon monoxide regulates the activity of cystathionine-?-lyase that generates H2S. Preliminary data show that the HA channel is a Ca2+-activated monovalent cation channel.
Aim 2 therefore tests the hypothesis that the HA channel is a Ca2+-sensitive TRP ion channel, and that H2S serves as a signal in hypoxia-induced activation of the HA channel.
Aim 3 tests the role of the HA channel as part of a positive feedback mechanism involved in the excitation of CB cells during moderate to severe hypoxia. The role of the HA channel in the activation of BK, as part of the negative feed-back mechanism to limit over- excitation is also tested. The contribution of the HA channel to CB cell excitation s studied using an inhibitor of the HA channel and mice lacking the TRP ion channel. The outcome of these experiments should establish the HA channel as a new target of hypoxia, and also help to define the role of H2S as a hypoxia-generated signal that modulates both TASK and the HA channel. These studies should fill an important knowledge gap in our understanding of the O2 sensing mechanisms by carotid body chemoreceptors.

Public Health Relevance

The goal of our research is to improve the understanding of how the specialized cells located at the carotid artery (carotid body cells) sense the decrease in oxygen level (hypoxia) in the blood and elicits a compensatory mechanism to regulate breathing. Better understanding of this mechanism is important for improving various abnormal respiratory conditions that arise due to the dysfunction of the carotid body.

National Institute of Health (NIH)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Lin, Sara
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Rosalind Franklin University of Medicine & Sci
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North Chicago
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Kim, Donghee; Kang, Dawon (2015) Role of K?p channels in stimulus-secretion coupling. Pflugers Arch 467:1001-11
Kang, Dawon; Wang, Jiaju; Hogan, James O et al. (2014) Increase in cytosolic Ca2+ produced by hypoxia and other depolarizing stimuli activates a non-selective cation channel in chemoreceptor cells of rat carotid body. J Physiol 592:1975-92
Kang, Dawon; Hogan, James O; Kim, Donghee (2014) THIK-1 (K2P13.1) is a small-conductance background K(+) channel in rat trigeminal ganglion neurons. Pflugers Arch 466:1289-300
Kim, Donghee; Kang, Dawon; Martin, Elizabeth A et al. (2014) Effects of modulators of AMP-activated protein kinase on TASK-1/3 and intracellular Ca(2+) concentration in rat carotid body glomus cells. Respir Physiol Neurobiol 195:19-26