The decreased expression of the nitric oxide (NO) receptor, soluble guanylyl cyclase (sGC), occurs in response to multiple stimuli in vivo and in cell culture and correlates with various disease states such as hypertension, inflammation and neurodegenerative disorders. The ability to understand and modulate sGC expression and cGMP levels in any of these conditions could be a valuable therapeutic tool. We demonstrate here that the c-Jun kinase inhibitor, SP600125, completely blocked the decreased expression of sGC₁ subunit mRNA by nerve growth factor (NGF) in PC12 cells. Inhibitors of the ERK and p38 MAPK pathways, PD98059 and SB203580, had no effect. SP600125 also inhibited the NGF-mediated decrease in expression of sGC₁ protein and sGC activity in PC12 cells. Other experiments revealed that decreased sGC₁ mRNA expression through a cAMP pathway, using forskolin, was not blocked by SP600125. We also demonstrate that TNF/IL-1-stimulation of rat lung fibroblast (RFL-6) cells resulted in sGC₁ mRNA inhibition, which was blocked by SP600125. Expression of a constitutively active JNKK2-JNK1 fusion protein in RFL-6 cells caused endogenous sGC₁ mRNA levels to decrease while a constitutively active ERK2 protein had no effect. Collectively, these data demonstrate that SP600125 may influence the intracellular levels of the sGC₁ subunit in certain cell types, and may implicate a role for c-Jun kinase in the regulation of sGC₁ expression.