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Activation of Phosphodiesterase IV During Desensitization of the A 2A Adenosine Receptor‐Mediated Cyclic AMP Response in Rat Pheochromocytoma (PC12) Cells
Author(s) -
Chang YuHsin,
Conti Marco,
Lee YiChao,
Lai HsingLin,
Ching YungHao,
Chern Yijuang
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69031300.x
Subject(s) - desensitization (medicine) , medicine , forskolin , endocrinology , adenosine , protein kinase a , phosphodiesterase , agonist , phosphodiesterase inhibitor , cyclic adenosine monophosphate , receptor , stimulation , chemistry , ibmx , homologous desensitization , adenosine receptor , biology , kinase , enzyme , biochemistry
Prolonged activation of an A 2A adenosine receptor significantly inhibits the cellular response to subsequent stimulation (A 2A desensitization). We have reported previously that activation of phosphodiesterase (PDE) contributes to A 2A desensitization in PC12 cells. In the present study, we show that a type IV PDE (PDE4)‐selective inhibitor (Ro 20‐1724) effectively blocks the increase in PDE activity in desensitized cells. Thus, PDE4 appears to be the PDE specifically activated during A 2A desensitization in PC12 cells. Prolonged treatment of PC12 cells with an A 2A ‐selective agonist (CGS21680) leads to increased PDE4 activity in a dose‐dependent manner, which can be blocked by an A 2A ‐selective antagonist [8‐(3‐chlorostyryl)caffeine]. Using two PDE4 antibodies, we were able to demonstrate that the levels of two PDE4‐immunoreactive bands (72 and 79 kDa) were increased significantly during A 2A desensitization. Prolonged treatment with forskolin to elevate intracellular cyclic AMP contents also resulted in increased PDE4 activity. In addition, activation of PDE4 activity during A 2A desensitization could be blocked by a protein kinase A (PKA)‐selective inhibitor (H89) and was not observed in a PKA‐deficient PC12 cell line (A123). Taken together, activation of PDE4 via a cyclic AMP/PKA‐dependent pathway plays a critical role in dampening the signal of the A 2A receptor.