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Inhibition of p38 Mitogen-Activated Protein Kinase Enhances Adrenergic-Stimulated Arylalkylamine N-Acetyltransferase Activity in Rat Pinealocytes

Departments of Physiology and Medicine (C.L.C.) Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

Address all correspondence and requests for reprints to: Dr. A. K. Ho, Department of Physiology, 7-26 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7. E-mail: anho{at}ualberta.ca.

We have previously shown that inhibition of p38^MAPK increases adrenergic-stimulated p42/44^MAPK activation in rat pinealocytes. In this study we investigated whether p38^MAPK played a role in the adrenergic regulation of arylalkylamine-N-acetyltransferase (AA-NAT) induction and melatonin (MT) synthesis. Treatment of pinealocytes with norepinephrine (NE) caused a time-dependent increase in the levels of AA-NAT mRNA, AA-NAT protein, and enzymatic activity as well as MT production. Cotreatment with SB202190, a selective p38^MAPK inhibitor, although having no effect on AA-NAT activity or protein level 3 h after NE treatment, caused a sustained increase in AA-NAT activity and protein level after 6 h of NE treatment. The increases in NE-stimulated AA-NAT activity and protein level by SB202190 occurred in the absence of an increase in AA-NAT mRNA. Similar results were obtained when AA-NAT was induced by (Bu)₂cAMP or when SB203580 was used to inhibit p38^MAPK. In comparison, SB202474, the inactive analog, had no effect on NE or (Bu)₂cAMP-stimulated AA-NAT activity or protein level. SB202190 also increased cumulative NE-stimulated MT production, provided that the medium was supplemented with 5-methoxytryptamine. p38^MAPK inhibitors had no effect on hydroxyindole-O>-methyltransferase activity. These results show that inhibition of p38^MAPK, although having no effect on cAMP-mediated AA-NAT transcription, appears to increase AA-NAT activity either by increasing translation or by reducing degradation of the AA-NAT protein. The lack of effect on NE-stimulated MT accumulation by p38^MAPK inhibitors in the absence of 5-methoxytryptamine could be secondary to a lack of substrate, or alternatively, hydroxyindole-O-methyltransferase may become limiting.

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