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Abstract
Nicotine, a major component of tobacco smoke, stimulates catecholamine secretion and activates catecholamine biosynthetic enzymes such as tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) in adrenal medullary cells. We investigated the effect of long term treatment with nicotine on TH and DBH gene expression in rat PC12 pheochromocytoma cells. Nicotine treatment for 1-2 days increased both the TH and DBH mRNA levels. The effect of nicotine on TH mRNA seems to be transcriptionally mediated. Deletion analysis of the 5' promoter region of the TH gene showed that the region containing a cyclic AMP/calcium regulatory element is sufficient for the nicotinic induction of TH. Nicotine did not induce TH mRNA or chloramphenicol acetyltransferase reporter activity in mutant PC12 cells deficient in protein kinase A activity. However, the deficiency in protein kinase A activity did not affect the elevation in intracellular calcium concentration caused by nicotine, indicating normal receptor function. These results suggest that a cAMP-mediated pathway plays a crucial role in the long term nicotine-induced activation of the TH gene.
Highlights
From the Departments of $Biochemistm and Molecular Bwbgy, and $Cell Biology and Anatomy, New York Medical College, Valhatla, New York 10595
The time course for the elevation of tyrosine hydroxylase (TH) and DBHmRNA levels following nicotine treatment is shown in Figs. 2 and 3, 1 0 20 30 40 50 60 70 80
The results of this study show that both T H and DBH mRNA levels can be regulated by nicotine treatment
Summary
From the Departments of $Biochemistm and Molecular Bwbgy, and $Cell Biology and Anatomy, New York Medical College, Valhatla, New York 10595. The effect of nicotine on TH adrenal medulla (Slotkin and Seidler, 1976; Fossom et al, 1991a).In uiuo stimulation of nicotinic acetylcholine receptors in the adrenal medulla is considered to be an important mechanism in trans-synapticregulation of catecholamine biosynthesis in response to various types of stressors such as cold, immobilization, insulin-induced hypoglycemia, and remRNA seems to be transcriptionally mediated. Maffin cells (Stachowiak et al, 1990a, 199Ob; Olasmaa et al, 1992; Craviso et al, 1992).T H gene expression, an important step for long term regulation of catecholamine biosynthesis, is alteredin response to a variety of stimuli, including various neuronal and hormonal factors, growth factors, and cell density
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