PT  - JOURNAL ARTICLE
AU  - Thomas, J M
AU  - Frazier, J S
AU  - Hu, Z W
AU  - Hoffman, B B
TI  - 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.
DP  - 1995 Oct 01
TA  - Molecular Pharmacology
PG  - 593--600
VI  - 48
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/48/4/593.short
4100  - http://molpharm.aspetjournals.org/content/48/4/593.full
SO  - Mol Pharmacol1995 Oct 01; 48
AB  - 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.