Mitogen-activated protein kinase phosphatase-1 (MKP-1) preferentially dephosphorylates p42/44MAPK but not p38MAPK in rat pinealocytes

J Neurochem. 2007 Jun;101(6):1685-93. doi: 10.1111/j.1471-4159.2007.04557.x. Epub 2007 Apr 16.

Abstract

We recently reported a diurnal and norepinephrine (NE) -induced expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) in the rat pineal gland and postulated that this MKP-1 expression might impact adrenergic-regulated arylalkylamine-N-acetyltransferase (AA-NAT) activity via modulation of MAPKs. In this study, we investigated the effect of depletion of MKP-1 expression by using doxorubicin, a topoisomerase inhibitor that suppresses the expression of MKP-1 in other cell types and small interfering RNA targeted against Mkp1 in NE-stimulated pinealocytes. We found that both treatments were effective in inhibiting NE induction of MKP-1 expression. Moreover, both treatments also resulted in a prolonged activation of p42/44MAPK and an increase in AA-NAT induction by NE. In contrast, treatment of pinealocytes with PD98059, an inhibitor of MAPK kinase, reduced NE-stimulated AA-NAT activity. Interestingly, suppressing MKP-1 expression had no effect on the time profile of NE-stimulated p38MAPK activation. These results indicate that MKP-1 modulates the profile of AA-NAT activity by selectively shaping the activation profile of p42/44MAPK but not that of p38MAPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arylalkylamine N-Acetyltransferase / biosynthesis
  • Cell Cycle Proteins / metabolism*
  • Doxorubicin / pharmacology
  • Dual Specificity Phosphatase 1
  • Enzyme Activation / drug effects
  • Enzyme Induction / drug effects
  • Flavonoids / pharmacology
  • Immediate-Early Proteins / metabolism*
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 2 / antagonists & inhibitors
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Norepinephrine / pharmacology
  • Phosphoprotein Phosphatases / metabolism*
  • Pineal Gland / cytology*
  • Pineal Gland / drug effects
  • Pineal Gland / enzymology*
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatases / metabolism*
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Cell Cycle Proteins
  • Flavonoids
  • Immediate-Early Proteins
  • RNA, Small Interfering
  • Doxorubicin
  • Arylalkylamine N-Acetyltransferase
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, rat
  • Protein Tyrosine Phosphatases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Norepinephrine