STIMULATION OF THE CYCLIC-GMP PATHWAY BY NO INDUCES EXPRESSION OF THEIMMEDIATE-EARLY GENES C-FOS AND JUNB IN PC12 CELLS

Stimulation of several second messenger pathways induces the expressio n of immediate early genes such as c-fos, c-jun, junB, and junD, but l ittle is known about their induction via the stimulation of the cyclic GMP pathway. Here we looked at the expression of early genes in pheoc hromocytoma PC12 cells after activation of cytosolic guanylate cyclase by sodium nitroprusside. This compound spontaneously releases NO, a m olecule known to be involved in cell communication. We found that expr ession of c-fos and junB but not of c-jun or junD is increased upon ac tivation of cyclic GMP pathway. c-fos mRNA expression was the most act ivated (fourfold at 30 min), whereas junB response was more modest (2. 2-fold activation at 60 min). Nuclear extracts of stimulated cells sho w increased binding capacity to the API binding site consistent with t he dose-response curve. The activating effect of nitroprusside could b e reproduced by dipyridamole, a selective cyclic GMP phosphodiesterase inhibitor and by 8-p-chlorophenylthio-cyclic GMP, a permeant selectiv e cyclic GMP-dependent protein kinase activator, and abolished by KT58 23, an inhibitor of that kinase. The results show that NO promotes ear ly gene activation and API binding enhancement through the stimulation of the cyclic GMP pathway.