Regulation of cAMP-induced arylalkylamine N-acetyltransferase, Period1, and MKP-1 gene expression by mitogen-activated protein kinases in the rat pineal gland

Brain Res Mol Brain Res. 2005 Oct 3;139(2):333-40. doi: 10.1016/j.molbrainres.2005.06.004.

Abstract

In rodent pineal glands, sympathetic innervation, which leads to norepinephrine release, is a key process in the circadian regulation of physiology and certain gene expressions. It has been shown that gene expression of the rate-limiting enzyme in the melatonin synthesis arylalkylamine N-acetyltransferase (Aa-Nat), circadian clock gene Period1, and mitogen-activated protein kinase (MAPK) phosphtase-1 (MKP-1), is controlled mainly by a norepinephrine-beta-adrenergic receptor-cAMP signaling cascade in the rat pineal gland. To further dissect the signaling cascades that regulate those gene expressions, we examined whether MAPKs are involved in cAMP-induced gene expression. Western blot and immunohistochemical analyses showed that one of the three MAPKs, c-Jun N-terminal kinase (JNK), was expressed in the pineal, and was phosphorylated by cAMP analogue stimulation with a peak 20 min after start of the stimulation, in vitro. A specific JNK inhibitor SP600125 (Anthra[1,9-cd]pyrazol-6(2H)-one1,9-pyrazoloanthrone), but not its negative control (N1-Methyl-1,9-pyrazoloanthrone), significantly reduced cAMP-stimulated Aa-Nat, Period1, and MKP-1 mRNA levels. Although another MAPK, p38(MAPK), has also been shown to be activated by cAMP stimulation, a p38(MAPK) inhibitor, SB203580 (4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole, HCl), showed no effect on cAMP-induced Aa-Nat and Period1 mRNA levels; whereas SB203580, but not its negative analogue SB202474 (4-Ethyl-2(p-methoxyphenyl)-5-(4'-pyridyl)-IH-imidazole, DiHCl), significantly reduced cAMP-induced MKP-1 mRNA levels. Taken together, our data suggest that cAMP-induced Aa-Nat and Period1 are likely to be mediated by activation of JNK, whereas MKP-1 may be mediated by both p38(MAPK) and JNK activations.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Anthracenes / pharmacology
  • Arylamine N-Acetyltransferase / genetics
  • Arylamine N-Acetyltransferase / metabolism*
  • Blotting, Western / methods
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cyclic AMP / pharmacology*
  • Drug Interactions
  • Dual Specificity Phosphatase 1
  • Enzyme Inhibitors / pharmacology
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / physiology
  • Imidazoles / pharmacology
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Immunohistochemistry / methods
  • MAP Kinase Kinase 4 / metabolism
  • Male
  • Mitogen-Activated Protein Kinases / pharmacology*
  • Molecular Weight
  • Organ Culture Techniques
  • Period Circadian Proteins
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Pineal Gland / drug effects*
  • Pineal Gland / metabolism
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Time Factors

Substances

  • Anthracenes
  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Eye Proteins
  • Imidazoles
  • Immediate-Early Proteins
  • Per1 protein, rat
  • Period Circadian Proteins
  • Pyridines
  • pyrazolanthrone
  • Cyclic AMP
  • Arylamine N-Acetyltransferase
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, rat
  • Protein Tyrosine Phosphatases
  • SB 203580