Tetrahydrobiopterin increases in adrenal medulla and cortex: a factor in the regulation of tyrosine hydroxylase.

Abstract

Tetrahydrobiopterin, the cofactor for tyrosine hydroxylase and other monooxygenases, is present in tissues at apparent concentrations much less than those necessary to saturate the corresponding enzymes. Reserpine treatment or insulininduced hypoglycemia in rats produces a statistically significant increase in the tetrahydrobiopterin content of both the adrenal medulla and the cortex. Adrenal denervation and hypophysectomy selectively block the increases in cofactor level in medulla and cortex, respectively, while cycloheximide prevents the increase in both tissues. Reserpine did not increase cofactor levels in liver, kidney, or corpus striatum but decreased that of the pineal gland. These results suggest that tetrahydrobiopterin is under neural control in the medulla and hormonal control in the cortex and that increases in cofactor may result from induction ofenzyme(s) in the biosynthetic pathway. These results demonstrate regulation of tissue tetrahydrobiopterin and are consistent with the suggestion that cofactor levels participate in the regulation of tyrosine hydroxylase in the adrenal medulla and may have a function, as yet undetermined, in the adrenal cortex.L-erythro-5,6,7,8-tetrahydrobiopterin (H4B) is an essential cofactor for tyrosine 3-monooxygenase [TyrOase; tyrosine hydroxylase; L-tyrosine, tetrahydropteridine:oxygen oxido reductase (3-hydroxylating); EC 1.14.16.2] (1), the rate-limiting enzyme in the biosynthesis ofthe neurotransmitters dopamine, norepinephrine, and epinephrine (2). There is considerable evidence for the short-term regulation oftyrosine hydroxylation by a decrease in the Km of TyrOase for its cofactor, H4B (for recent reviews, see refs. 3 and 4). Delayed or long-term regulation of tyrosine hydroxylation and catecholamine synthesis is obtained by increased synthesis ofTyrOase, dopamine-,B-hydroxylase, and catecholamine storage vesicles (5, 6). Several lines of evidence suggest that H4B is present in concentrations substantially less than Km for TyrOase in monoaminergic neurons. The administration of exogenous cofactor results in enhanced hydroxylation in rat striatum in vivo (7), in cultures of sympathetic neurons (8), in striatal synaptosomes (9), and in the isolated hypogastric nerve-vas deferens preparation (10, 11). A second line of evidence is the increase in dopamine synthesis produced by cyclic AMP or stimulation of catecholaminergic terminals that apparently is the result of the increased affnity of TyrOase for the pterin cofactor (12-15). Finally, induction ofrat hypothalamus TyrOase by reserpine administration failed to enhance tyrosine hydroxylation in synaptosomes prepared from this tissue (16) unless exogenous H4B was added to the incubation medium (17). Although regulation of monoamine synthesis through changes in the availability of reduced biopterin has been proposed (18), there is no experimental evidence for physiological regulation of endogenous cofactor levels. The long-term regulation of catecholamine synthesis could create a paradoxical situation if t...

Human Tyrosine Hydroxylase Isoforms

“…The K i values for BH 4 were 24.7 and 53.0 M for hTH3 and hTH1, respectively. The physiological concentration of BH 4 has been estimated to be in the range of 1 to 13 M in catecholamine tissues of various species (33)(34)(35). These data suggest that in vivo the activity of hTH3 and hTH1 is optimal.…”

Induction of Adrenal Tyrosine Hydroxylase mRNA by Single Immobilization Stress Occurs Even After Splanchnic Transection and in the Presence of Cholinergic Antagonists

“…Pronounced increases in the BH4 levels in rat adrenal medulla were observed after exposure to various stressors, e.g., insulin-induced hypoglycemia, reserpine-induced CA depletion (Abou-Donia and Viveros, 1980;Viveros et al, 1981), and cold exposure (Baruchin et al, 1990). Splanchnic transection blocks both the increase in BH4 levels and activity of its ratelimiting biosynthetic enzyme, GTP cyclohydrolase, in the adrenal medulla of the insulin-treated rats (Abou- Donia and Viveros, 1980;Viveros et al, 1981). Splanchnic innervation may be essential for regulation of BH4 levels and its synthesis in the adrenal medulla of rats stressed by IMO.…”

“…The concentration of BH4 cofactor in the adrenal medulla appears to be rate limiting for tyrosine hydroxylation (luvone et al, 1985) and changes in BH4 levels may play a key role in the regulation of CA synthesis (Abou-Donia et al, 1986). Pronounced increases in the BH4 levels in rat adrenal medulla were observed after exposure to various stressors, e.g., insulin-induced hypoglycemia, reserpine-induced CA depletion (Abou-Donia and Viveros, 1980;Viveros et al, 1981), and cold exposure (Baruchin et al, 1990). Splanchnic transection blocks both the increase in BH4 levels and activity of its ratelimiting biosynthetic enzyme, GTP cyclohydrolase, in the adrenal medulla of the insulin-treated rats (Abou- Donia and Viveros, 1980;Viveros et al, 1981).…”

Purification and Cloning of the GTP Cyclohydrolase I Feedback Regulatory Protein, GFRP

“…In the adrenal medulla and cortex, catecholamine synthesis as well as BH 4 levels and GTP cyclohydrolase I activity have been shown to be hormonally regulated (6), probably through the action of cAMP-mediated pathways leading to increased protein synthesis (7). Recently, reserpine, which had previously been found to increase BH 4 levels and GTP cyclohydrolase I activity in the adrenal cortex (8), was shown to increase levels of GTP cyclohydrolase I mRNA in peripheral and central neurons (9). Activation of the immune system results in the production of interferon-␥ which then stimulates an increase in GTP cyclohydrolase I activity in macrophages resulting in increased extracellular dihydroneopterin levels in humans and intracellular BH 4 levels and BH 4 -dependent nitric oxide synthesis in rodents (10).…”