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J. Biol. Chem., Vol. 277, Issue 37, 33930-33942, September 13, 2002

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Essential Role of cAMP-response Element-binding Protein Activation by A_2A Adenosine Receptors in Rescuing the Nerve Growth Factor-induced Neurite Outgrowth Impaired by Blockage of the MAPK Cascade^*

Hsiao-Chun Cheng^§, Hsiu-Ming Shih^¶, and Yijuang Chern

From the  Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, ^§ Institute of Neuroscience, National Yang-Ming University, Taipei 11221, Taiwan, and ^¶ Division of Molecular and Genomic Medicine, National Health Research Institutes, Taipei 11529, Taiwan, Republic of China

We found in the present study that stimulation of the A_2A adenosine receptor (A_2A-R) using an A_2A-selective agonist (CGS21680) rescued the blockage of nerve growth factor (NGF)-induced neurite outgrowth when the NGF-evoked MAPK cascade was suppressed by an MEK inhibitor (PD98059) or by a dominant-negative MAPK mutant (dnMAPK). This action of A_2A-R (designated as the A_2A-rescue effect) can be blocked by two inhibitors of protein kinase A (PKA) and was absent in a PKA-deficient PC12 variant. Activation of the cAMP/PKA pathway by forskolin exerted the same effect as that by A_2A-R stimulation. PKA, thus, appears to mediate the A_2A-rescue effect. Results from cAMP-response element-binding protein (CREB) phosphorylation at serine 133, trans-reporting assays, and overexpression of two dominant-negative CREB mutants revealed that A_2A-R stimulation led to activation of CREB in a PKA-dependent manner and subsequently reversed the damage of NGF-evoked neurite outgrowth by PD98059 or dnMAPK. Expression of an active mutant of CREB readily rescued the NGF-induced neurite outgrowth impaired by dnMAPK, further strengthening the importance of CREB in the NGF-mediated neurite outgrowth process. Moreover, simultaneous activation of the A_2A-R/PKA/CREB-mediated and the phosphatidylinositol 3-kinase pathways caused neurite outgrowth that was not suppressed by a selective inhibitor of TrkA, indicating that transactivation of TrkA was not involved. Collectively, CREB functions in conjunction with the phosphatidylinositol 3-kinase pathway to mediate the neurite outgrowth process in PC12 cells.

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