Gq-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, S
487
TR and S
487
A, in which the Ser
487
residue of C-terminal was truncated or mutated to alanine, respectively. We have found that S
487
TR and S
487
A 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 S
487
TR and S
487
A. In cells expressing S
487
TR, histamine transiently induced ERK phosphorylation, which were suppressed by intracellular Ca
2+ 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 S
487
A, which were suppressed by inhibitors of GRK, clathrin, Raf and MEK but not intracellular Ca
2+ chelator and PKC inhibitors. These results suggest that progressive processes of the H
1-receptor-mediated ERK phosphorylation might be differentially regulated by the G
q-protein/Ca
2+/PKC- and GRK/β-arrestin/clathrin/Raf/MEK-dependent pathways.
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