Norepinephrine induction of mitogen-activated protein kinase phosphatase-1 expression in rat pinealocytes: distinct roles of alpha- and beta-adrenergic receptors.

Abstract

In this study, we investigated the mechanisms through which norepinephrine (NE) regulates MAPK phosphatase-1 (MKP-1) expression in rat pinealocytes. Stimulation with NE (a mixed alpha- and beta-adrenergic agonist) caused a rapid increase in MKP-1 mRNA and protein that peaked around 1 h post stimulation, and the response was sustained for at least 4 h. Selective activation of beta-adrenergic receptors with isoproterenol for 1 h caused a similar increase in MKP-1 mRNA and protein as observed with NE, but at 3 h, the isoproterenol response was much lower relative to NE. In contrast, selective activation of alpha-adrenergic receptors caused only small increases in MKP-1 mRNA and protein and appeared to function primarily in prolonging the beta-adrenergic-stimulated responses. In NE-stimulated pinealocytes, blockade of beta-adrenergic receptors caused a rapid reduction in MKP-1 mRNA, but it had a minimal effect on MKP-1 protein. In contrast, blockade of alpha-adrenergic receptors specifically reduced NE-induced MKP-1 protein but not mRNA. At the postreceptor level, treatment with dibutyryl cAMP caused parallel increases in MKP-1 mRNA and protein. However, treatment with a protein kinase C activator caused a significant increase in MKP-1 protein but had little effect on MKP-1 mRNA. Together, these results suggest that, in rat pinealocytes, NE activates the beta-adrenergic receptor --> protein kinase A pathway to induce transcription and translation of MKP-1 expression and the alpha-adrenergic receptor --> protein kinase C pathway to prolong the stimulated responses through increased stability of the MKP-1 protein.