THE 2ND-MESSENGER, CYCLIC-AMP, IS NOT SUFFICIENT FOR MYELIN GENE INDUCTION IN THE PERIPHERAL NERVOUS-SYSTEM

The adenylyl cyclase-cyclic AMP (cAMP) second messenger pathway has be en proposed to regulate myelin gene expression; however, a clear corre lation between endogenous cAMP levels and myelin-specific mRNA levels has never been demonstrated during the induction or maintenance of dif ferentiation by the myelinating Schwann cell. Endogenous cAMP levels d ecreased to 8-10% of normal nerve by 3 days after crush or permanent t ransection injury of adult rat sciatic nerve. Whereas levels remained low after transection injury, cAMP levels reached only 27% of the norm al values by 35 days after crush injury. Because P-o mRNA levels were 60% of normal levels by 14 days and 100% by 21 days after crush injury , cAMP increased only well after Po gene induction. cAMP, therefore, d oes not appear to trigger myelin gene induction but may be involved in myelin assembly or maintenance. Forskolin, an activator of adenylyl c yclase, increased endoneurial cAMP levels only in the normal nerve, an d in the crushed nerve beginning at 16 days after injury, but at no ti me in the transected nerve. Only by treating transected nerve with 3-i sobutyl-1-methylxanthine (IBMX), an inhibitor of cAMP phosphodiesteras es, in combination with forskolin was it possible to increase cAMP lev els. No induction of myelin genes, however, was observed with short- o r long-term treatment with IBMX and forskolin in the transected nerve. A threefold increase in phosphodiesterase activity was observed at 35 days after both injuries, and a nonmyelinated nerve was shown to have even higher activity. These experiments, therefore, suggest an import ant role for phosphodiesterase in the inactivation of this second mess enger-dependent stimuli when Schwann cells are nonmyelinating, such as after sciatic nerve injury or in the nonmyelinated nerve, which again implies that cAMP may be required for the maintenance of the myelin s heath.