Norepinephrine induction of mitogen-activated protein kinase phosphatase-1 expression in rat pinealocytes: distinct roles of alpha- and beta-adrenergic receptors.
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.
Price
Donald M
DM
Department of Physiology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
Chik
Constance L
CL
Ho
Anthony K
AK
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D010870:Pineal Gland / Q000166:cytology / Q000201:enzymology*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013566:Sympathomimetics / Q000494:pharmacology*
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D013566:Sympathomimetics; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases; D009638:Norepinephrine