G_q-protein-coupled histamine H₁ receptors play a key role for allergic and inflammatory reactions. We constructed two differential C-terminal mutants of human H₁ receptors, S487TR and S487A, in which the Ser487 residue of C-terminal was truncated or mutated to alanine, respectively. We have found that S487TR and S487A selectively couples to G_q-protein and β-arrestin, respectively. In this study, we investigated histamine-induced and G_q-protein/β-arrestin-mediated ERK phosphorylation in Chinese hamster ovary cells expressing S487TR and S487A. In cells expressing S487TR, histamine transiently induced ERK phosphorylation, which were suppressed by intracellular Ca²⁺ chelator and inhibitors of protein kinase C (PKC) but not inhibitors of G-protein-coupled receptor kinase (GRK), clathrin, Raf and MEK. In contrast, histamine sustainably induced ERK phosphorylation in cells expressing S487A, which were suppressed by inhibitors of GRK, clathrin, Raf and MEK but not intracellular Ca²⁺ chelator and PKC inhibitors. These results suggest that progressive processes of the H₁-receptor-mediated ERK phosphorylation might be differentially regulated by the G_q-protein/Ca²⁺/PKC- and GRK/β-arrestin/clathrin/Raf/MEK-dependent pathways.