Under several adverse conditions, such as hypoxia or ischaemia, extracellular levels of adenosine are elevated because of increased energy demands and ATP metabolism. Because extracellular adenosine affects metabolism through G-protein-coupled receptors, its regulation is of high adaptive importance. CNT2 (concentrative nucleoside transporter 2) may play physiological roles beyond nucleoside salvage in brain as it does in other tissues. Even though nucleoside transport in brain has mostly been seen as being of equilibrative-type, in the present study, we prove that the rat phaeochromocytoma cell line PC12 shows a concentrative adenosine transport of CNT2-type when cells are differentiated to a neuronal phenotype by treatment with NGF (nerve growth factor). Differentiation of PC12 cells was also associated with the up-regulation of adenosine A1 receptors. Addition of adenosine receptor agonists to cell cultures increased CNT2-related activity by a mechanism consistent with A1 and A2A receptor activation. The addition of adenosine to the culture medium also induced the phosphorylation of the intracellular regulatory kinase AMPK (AMP-activated protein kinase), with this effect being dependent upon adenosine transport. CNT2-related activity of differentiated PC12 cells was also dramatically down-regulated under hypoxic conditions. Interestingly, the analysis of nucleoside transporter expression after experimental focal ischaemia in rat brain showed that CNT2 expression was down-regulated in the infarcted tissue, with this effect somehow being restricted to other adenosine transporter proteins such as CNT3 and ENT1 (equilibrative nucleoside transporter 1). In summary, CNT2 is likely to modulate extracellular adenosine and cell energy balance in neuronal tissue.
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Research Article|
August 29 2013
Hypoxia and P1 receptor activation regulate the high-affinity concentrative adenosine transporter CNT2 in differentiated neuronal PC12 cells
Lorena Medina-Pulido;
Lorena Medina-Pulido
*Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona (IBUB), and CIBER EHD, 08028 Barcelona, Spain
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Míriam Molina-Arcas;
Míriam Molina-Arcas
1
*Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona (IBUB), and CIBER EHD, 08028 Barcelona, Spain
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Carles Justicia;
Carles Justicia
†Departament d’Isquèmia Cerebral i Neurodegeneració, Institut d’Investigaciones Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), 08036 Barcelona, Spain
‡Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
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Eduardo Soriano;
Eduardo Soriano
§Departament de Biologia Cel·lular, Universitat de Barcelona, and CIBER NED, 08028 Barcelona, Spain
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Ferran Burgaya;
Ferran Burgaya
§Departament de Biologia Cel·lular, Universitat de Barcelona, and CIBER NED, 08028 Barcelona, Spain
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Anna M. Planas;
Anna M. Planas
†Departament d’Isquèmia Cerebral i Neurodegeneració, Institut d’Investigaciones Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), 08036 Barcelona, Spain
‡Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
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Marçal Pastor-Anglada
Marçal Pastor-Anglada
2
*Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona (IBUB), and CIBER EHD, 08028 Barcelona, Spain
2To whom correspondence should be addressed (email mpastor@ub.edu).
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Publisher: Portland Press Ltd
Received:
February 14 2013
Revision Received:
June 25 2013
Accepted:
July 03 2013
Accepted Manuscript online:
July 03 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 454 (3): 437–445.
Article history
Received:
February 14 2013
Revision Received:
June 25 2013
Accepted:
July 03 2013
Accepted Manuscript online:
July 03 2013
Citation
Lorena Medina-Pulido, Míriam Molina-Arcas, Carles Justicia, Eduardo Soriano, Ferran Burgaya, Anna M. Planas, Marçal Pastor-Anglada; Hypoxia and P1 receptor activation regulate the high-affinity concentrative adenosine transporter CNT2 in differentiated neuronal PC12 cells. Biochem J 15 September 2013; 454 (3): 437–445. doi: https://doi.org/10.1042/BJ20130231
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