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Physiology and effects of nucleosides in mice lacking all four adenosine receptors

Adenosine is a constituent of many molecules of life; increased free extracellular adenosine indicates cell damage or metabolic stress. The importance of adenosine signaling in basal physiology, as opposed to adaptive responses to danger/damage situations, is unclear. We generated mice lacking all f...

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Autores principales: Xiao, Cuiying, Liu, Naili, Jacobson, Kenneth A., Gavrilova, Oksana, Reitman, Marc L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415873/
https://www.ncbi.nlm.nih.gov/pubmed/30822301
http://dx.doi.org/10.1371/journal.pbio.3000161
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author Xiao, Cuiying
Liu, Naili
Jacobson, Kenneth A.
Gavrilova, Oksana
Reitman, Marc L.
author_facet Xiao, Cuiying
Liu, Naili
Jacobson, Kenneth A.
Gavrilova, Oksana
Reitman, Marc L.
author_sort Xiao, Cuiying
collection PubMed
description Adenosine is a constituent of many molecules of life; increased free extracellular adenosine indicates cell damage or metabolic stress. The importance of adenosine signaling in basal physiology, as opposed to adaptive responses to danger/damage situations, is unclear. We generated mice lacking all four adenosine receptors (ARs), Adora1(−/−);Adora2a(−/−);Adora2b(−/−);Adora3(−/−) (quad knockout [QKO]), to enable investigation of the AR dependence of physiologic processes, focusing on body temperature. The QKO mice demonstrate that ARs are not required for growth, metabolism, breeding, and body temperature regulation (diurnal variation, response to stress, and torpor). However, the mice showed decreased survival starting at about 15 weeks of age. While adenosine agonists cause profound hypothermia via each AR, adenosine did not cause hypothermia (or bradycardia or hypotension) in QKO mice, indicating that AR-independent signals do not contribute to adenosine-induced hypothermia. The hypothermia elicited by adenosine kinase inhibition (with A134974), inosine, or uridine also required ARs, as each was abolished in the QKO mice. The proposed mechanism for uridine-induced hypothermia is inhibition of adenosine transport by uridine, increasing local extracellular adenosine levels. In contrast, adenosine 5′-monophosphate (AMP)–induced hypothermia was attenuated in QKO mice, demonstrating roles for both AR-dependent and AR-independent mechanisms in this process. The physiology of the QKO mice appears to be the sum of the individual knockout mice, without clear evidence for synergy, indicating that the actions of the four ARs are generally complementary. The phenotype of the QKO mice suggests that, while extracellular adenosine is a signal of stress, damage, and/or danger, it is less important for baseline regulation of body temperature.
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spelling pubmed-64158732019-04-01 Physiology and effects of nucleosides in mice lacking all four adenosine receptors Xiao, Cuiying Liu, Naili Jacobson, Kenneth A. Gavrilova, Oksana Reitman, Marc L. PLoS Biol Research Article Adenosine is a constituent of many molecules of life; increased free extracellular adenosine indicates cell damage or metabolic stress. The importance of adenosine signaling in basal physiology, as opposed to adaptive responses to danger/damage situations, is unclear. We generated mice lacking all four adenosine receptors (ARs), Adora1(−/−);Adora2a(−/−);Adora2b(−/−);Adora3(−/−) (quad knockout [QKO]), to enable investigation of the AR dependence of physiologic processes, focusing on body temperature. The QKO mice demonstrate that ARs are not required for growth, metabolism, breeding, and body temperature regulation (diurnal variation, response to stress, and torpor). However, the mice showed decreased survival starting at about 15 weeks of age. While adenosine agonists cause profound hypothermia via each AR, adenosine did not cause hypothermia (or bradycardia or hypotension) in QKO mice, indicating that AR-independent signals do not contribute to adenosine-induced hypothermia. The hypothermia elicited by adenosine kinase inhibition (with A134974), inosine, or uridine also required ARs, as each was abolished in the QKO mice. The proposed mechanism for uridine-induced hypothermia is inhibition of adenosine transport by uridine, increasing local extracellular adenosine levels. In contrast, adenosine 5′-monophosphate (AMP)–induced hypothermia was attenuated in QKO mice, demonstrating roles for both AR-dependent and AR-independent mechanisms in this process. The physiology of the QKO mice appears to be the sum of the individual knockout mice, without clear evidence for synergy, indicating that the actions of the four ARs are generally complementary. The phenotype of the QKO mice suggests that, while extracellular adenosine is a signal of stress, damage, and/or danger, it is less important for baseline regulation of body temperature. Public Library of Science 2019-03-01 /pmc/articles/PMC6415873/ /pubmed/30822301 http://dx.doi.org/10.1371/journal.pbio.3000161 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Xiao, Cuiying
Liu, Naili
Jacobson, Kenneth A.
Gavrilova, Oksana
Reitman, Marc L.
Physiology and effects of nucleosides in mice lacking all four adenosine receptors
title Physiology and effects of nucleosides in mice lacking all four adenosine receptors
title_full Physiology and effects of nucleosides in mice lacking all four adenosine receptors
title_fullStr Physiology and effects of nucleosides in mice lacking all four adenosine receptors
title_full_unstemmed Physiology and effects of nucleosides in mice lacking all four adenosine receptors
title_short Physiology and effects of nucleosides in mice lacking all four adenosine receptors
title_sort physiology and effects of nucleosides in mice lacking all four adenosine receptors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415873/
https://www.ncbi.nlm.nih.gov/pubmed/30822301
http://dx.doi.org/10.1371/journal.pbio.3000161
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