ACELL June 47/6

Wang, L. D., M. Wang, A. Todisco, E. Grand, and J. Del Valle. The human histamine H2 receptor regulates c-jun and c-fos in a differential manner. Am J Physiol Cell Physiol 278: C1246–C1255, 2000.—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 6 86.8% of control). The protein kinase C (PKC) inhibitors staurosporine (1026 M) and GF109203X (1026 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 (1024 M) stimulated extracellularly regulated kinase 2 tyrosine phosphorylation. The specific inhibitor of the mitogen-activated protein (MAP) kinase pathway, PD-98059 (5 3 1025 M), significantly inhibited histamine-induced c-fos and c-jun mRNA. Of interest, the p70 S6 kinase inhibitor rapamycin (1026 M) but not wortmannin decreased histamine-stimulated c-jun mRNA by 58.5 6 12% (mean 6 SE, n 5 4) while not significantly altering c-fos message. Histamine (1024 M) also led to an ,4.5-fold increase in Jun NH2-terminal kinase activity in a PKC-, PKA-, and MAP kinase-independent but rapamycinsensitive 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.