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Abstract

Phosphorylation of cyclic AMP response element-binding protein and induction of c-fos gene expression on withdrawal from chronic treatment with carbachol in NG108-15 cells.

J M Thomas, J S Frazier, Z W Hu and B B Hoffman
Molecular Pharmacology October 1995, 48 (4) 593-600;
J M Thomas
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J S Frazier
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Z W Hu
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B B Hoffman
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Abstract

Alterations in adenylyl cyclase activity in cultured cells after prolonged exposure to drugs such as morphine have been extensively studied as models for drug tolerance and withdrawal. NG108-15 cells develop increased intracellular cAMP concentrations after abrupt withdrawal from chronic treatment with the muscarinic cholinergic agonist carbachol. To determine whether this withdrawal-induced increase in cAMP modifies gene expression, we studied phosphorylation of the cAMP response element-binding protein (CREB) and expression of the c-fos gene, known to contain a cAMP response element, in NG108-15 cells after abrupt withdrawal from chronic treatment with carbachol. Prostaglandin E1, which activates adenylyl cyclase, caused concentration-dependent increases in the phosphorylation of CREB and in the abundance of c-fos mRNA. These changes occurred with small increments in cAMP accumulation. In cells treated with carbachol for 48 hr, induction of withdrawal with the muscarinic antagonist atropine led to a small increase in intracellular cAMP concentration but an 11.6-fold increase in the phosphorylation of CREB and a 3.4-fold increase in accumulation of c-fos mRNA. The adenylyl cyclase inhibitor 2',5'-dideoxyadenosine, which attenuated the chronic carbachol-induced increase in cAMP concentration, prevented the increased phosphorylation of CREB and the enhanced accumulation of c-fos mRNA during atropine-induced withdrawal. These results indicate that expression of the c-fos gene is induced by the small increments in cAMP concentration that can occur in cells on withdrawal from chronic treatment with drugs such as muscarinic agonists.

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Molecular Pharmacology
Vol. 48, Issue 4
1 Oct 1995
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Abstract

Phosphorylation of cyclic AMP response element-binding protein and induction of c-fos gene expression on withdrawal from chronic treatment with carbachol in NG108-15 cells.

J M Thomas, J S Frazier, Z W Hu and B B Hoffman
Molecular Pharmacology October 1, 1995, 48 (4) 593-600;

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Abstract

Phosphorylation of cyclic AMP response element-binding protein and induction of c-fos gene expression on withdrawal from chronic treatment with carbachol in NG108-15 cells.

J M Thomas, J S Frazier, Z W Hu and B B Hoffman
Molecular Pharmacology October 1, 1995, 48 (4) 593-600;
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