Regulation of alkaline phosphatase activity by p38 MAP kinase in response to activation of Gi protein-coupled receptors by epinephrine in osteoblast-like cells

The signaling mechanisms responsible for the regulation of alkaline phospha tase (ALP) activity by exogenous factors in osteoblastlike cells remain poo rly understood. Among various agents, epinephrine was recently found to inc rease ALP activity in differentiating MC3T3-E1 cells by stimulating alpha 1 adrenergic receptors coupled to Gi proteins. In the present study, we inve stigated the role of both ERK2 and p38 mitogen-activated protein (MAP) kina ses in mediating this response in MC3T3-E1 cells. Our results indicate that both MAP kinases are transiently stimulated by epinephrine in differentiat ing cells via a pertussis toxin sensitive mechanism. The role of each MAP k inase pathway in mediating the stimulation of ALP activity by epinephrine w as investigated using specific inhibitors. The MEK inhibitor PD98059, block ed ERK2 activity induced by epinephrine but had no effect on the stimulatio n of ALP activity. In contrast, low concentrations of SB203580, a specific inhibitor of the p38 MAP kinase, completely blunted this cellular response. However, this inhibitor had no influence on the stimulation of ALP activit y induced by ascorbic acid. In conclusion, the results of this study sugges t distinct roles for ERK and p38 MAP kinase pathways in regulating activity of MC3T3-E1 osteoblastic cells. The ERK pathway is likely involved in the control of cell proliferation whereas the p38 MAP kinase pathway regulates ALP activity in response to activation of Gi protein-coupled receptors.