Cyclic GMP (cGMP) has been characterized as a critical, pluripotent second messenger in peripheral tissues. Its effects are particularly important to the regulation of excitable cells such as cardiac and smooth muscle secretory cells. Cyclic GMP also undergoes dramatic fluctuations in the brain in response to excitatory neurotransmission. Recent work has only begun to delineate acute actions of these cGMP elevations on CNS neuronal activity; however, the longterm effects of cGMP on cellular phenotype have been largely unexplored. Preliminary data indicate that cGMP can regulate the activity of transcription factors which bind kB enhancer sequences. Such kB-binding factors have been implicated in control of expression of a diverse array of genes including cell attachment factors, cytokines, and antioxidant enzymes. In addition, several cytokines, as well as cellular oxidation, can activate kB-binding transcription factors. The potential involvement of cytokines in inflammatory brain damage -- and of oxidative insults in a myriad of brain disorders -- has created much interest in the regulation of kB-binding factors in the brain.

The studies proposed will test the hypothesis that cGMP can modulate kB- binding factor activity in neuronal cells. Furthermore, these studies will address the possibility that cGMP plays a role in the inductions of kB-dependent transcription effected by several stimuli, including glutamate and cellular oxidation. Specifically, attempts will be made to (1) identify the protein which is induced by cGMP to bind kB enhancers, (2) delineate the mechanistic relationship between cGMP- dependent protein kinase and activity of kB-binding factors, and (3) determine the individual genes activated by cGMP-inducible kB-binding factors in neuronal cells.

R29NS035872

1996-04-01

2001-03-31