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Adenosine A 2 A receptor but not HIF‐1 mediates Tyrosine hydroxylase induction in hypoxic PC12 cells
Author(s) -
Gammella Elena,
Cairo Gaetano,
Tacchini Lorenza
Publication year - 2010
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22366
Subject(s) - adenosine , creb , cyclic amp response element binding protein , adenosine a3 receptor , transfection , biology , microbiology and biotechnology , tyrosine hydroxylase , response element , medicine , transcription factor , endocrinology , agonist , adenosine receptor , receptor , gene expression , promoter , biochemistry , gene , dopamine
Tyrosine hydroxylase (TH) is the rate‐limiting enzyme in the biosynthesis of catecholamines released by oxygen‐sensitive cells in response to hypoxic conditions. Adenosine is released in response to hypoxia in the central nervous system and CGS21680, an adenosine A 2 A receptor agonist, induces TH transcription. As we have previously demonstrated the A 2 A receptor‐mediated induction of HIF‐1 in macrophages and hepatocytes, we investigated the involvement of HIF‐1 in the adenosine‐mediated activation of TH expression. Exposure to adenosine or CGS21680 increased TH mRNA and protein levels in PC12 cells. Transcription of a reporter gene under the control of the wild type rat TH promoter was induced 3.5‐fold in CGS21680‐treated cells, but neither the mutation of the hypoxia responsive element in the TH promoter nor the co‐transfection of a dominant negative of the HIF‐1 β subunit prevented the increase in transcription; furthermore, CGS21680 increased CREB binding activity but did not induce HIF‐1 DNA binding activity or protein levels. To investigate whether HIF‐1 was involved in the hypoxia‐mediated induction of TH, PC12 cells were exposed to hypoxia in the presence of the A 2 A receptor antagonist ZM241385, which prevented hypoxia‐dependent TH induction despite HIF‐1 activation; in line with this finding, the inhibition of HIF‐1 did not abolish TH induction in hypoxic PC12 cells. These results indicate that, under hypoxic conditions, TH (a key factor in systemic adaptation to reduced oxygen availability) is not regulated by HIF‐1, the primary modulator of the response to hypoxia, but by the adenosine A 2 A receptor‐mediated signalling pathway. © 2010 Wiley‐Liss, Inc.