The mitogen‐activated protein kinases (MAPKs) consist of the p42/p44 MAPKs and the stress‐activated protein kinases, c‐Jun N‐terminal kinase (JNK) and p38 MAPK. In this study we have examined the effect of histamine H₁ receptor activation on MAPK pathway activation in the smooth muscle cell line DDT₁MF‐2.

Histamine stimulated time and concentration‐dependent increases in p42/p44 MAPK activation in DDT₁MF‐2 cells. Responses to histamine were inhibited by the histamine H₁ receptor antagonist mepyramine (K_D 3.5 nM) and following pre‐treatment with pertussis toxin (PTX; 57% inhibition).

Histamine‐induced increases in p42/p44 MAPK activation were blocked by inhibitors of MAPK kinase 1 (PD 98059), tyrosine kinase (genistein and tyrphostin A47), phosphatidylinositol 3‐kinase (wortmannin and LY 294002) and protein kinase C (Ro 31‐8220; 10 μM; 41% inhibition). Inhibitors of Src tyrosine kinase (PP2) and the epidermal growth factor tyrosine kinase (AG1478) were without effect. Removal of extracellular Ca²⁺, chelation of intracellular Ca²⁺ with BAPTA and inhibition of focal adhesion assembly (cytochalasin D) had no significant effect on histamine‐induced p42/p44 MAPK activation.

Histamine stimulated time and concentration‐dependent increases in p38 MAPK activation in DDT₁MF‐2 cells but had no effect on JNK activation. Histamine‐induced p38 MAPK activation was inhibited by pertussis toxin (74% inhibition) and the p38 MAPK inhibitor SB 203580 (95% inhibition).

In summary, we have shown the histamine H₁ receptor activates p42/p44 MAPK and p38 MAPK signalling pathways in DDT₁MF‐2 smooth muscle cells. Interestingly, signalling to both pathways appears to involve histamine H₁ receptor coupling to G_i/G_o‐proteins.