Previously, we demonstrated that activation of the human H₂ receptor (hH₂R) leads to an increase in c-fos transcription and cell proliferation. The purpose of these studies was to examine whether hH₂R regulates c-jun expression and, if so, explore the mechanisms by which it does so. Histamine induced an increase in c-jun mRNA in human embryonic kidney cells stably transfected with the hH₂R (maximal effect: 554.6 ± 86.8% of control). The protein kinase C (PKC) inhibitors staurosporine (10⁶ M) and GF-109203X (10⁶ M) significantly inhibited histamine-stimulated c-fos mRNA while not altering c-jun expression. The protein kinase A (PKA) pathway inhibitors Rp-cAMP and protein kinase inhibitor did not affect the action of histamine on c-jun or c-fos mRNA. Histamine (10⁴ M) stimulated extracellularly regulated kinase 2 tyrosine phosphorylation. The specific inhibitor of the mitogen-activated protein (MAP) kinase pathway, PD-98059 (5 × 10⁵ M), significantly inhibited histamine-induced c-fos and c-jun mRNA. Of interest, the p70 S6 kinase inhibitor rapamycin (10⁶ M) but not wortmannin decreased histamine-stimulated c-jun mRNA by 58.5 ± 12% (mean ± SE, n = 4) while not significantly altering c-fos message. Histamine (10⁴ M) also led to an ~4.5-fold increase in Jun NH₂-terminal kinase activity in a PKC-, PKA-, and MAP kinase-independent but rapamycin-sensitive manner. Our findings suggest that histamine stimulates both c-fos and c-jun mRNA in a differential manner. PKC is involved in histamine-mediated c-fos activation, whereas p70 S6 kinase is important for linkage of this receptor to c-jun.