Activation of the p38 and p42/p44 mitogen‐activated protein kinase families by the histamine H 1 receptor in DDT 1 MF‐2 cells

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 H 1 receptor activation on MAPK pathway activation in the smooth muscle cell line DDT 1 MF‐2. Histamine stimulated time and concentration‐dependent increases in p42/p44 MAPK activation in DDT 1 MF‐2 cells. Responses to histamine were inhibited by the histamine H 1 receptor antagonist mepyramine (K D 3.5 n M ) 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 μ M ; 41% inhibition). Inhibitors of Src tyrosine kinase (PP2) and the epidermal growth factor tyrosine kinase (AG1478) were without effect. Removal of extracellular Ca 2+ , chelation of intracellular Ca 2+ 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 DDT 1 MF‐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 H 1 receptor activates p42/p44 MAPK and p38 MAPK signalling pathways in DDT 1 MF‐2 smooth muscle cells. Interestingly, signalling to both pathways appears to involve histamine H 1 receptor coupling to G i /G o ‐proteins.British Journal of Pharmacology (2001) 133 , 1378–1386; doi: 10.1038/sj.bjp.0704200