Pineal N -Acetyltransferase Activity: Effect of Sympathetic Stimulation

Stimulation by isoproterenol causes large increases in the activity of rat pineal N-acetyltransferase (arylamine acetyltransferase or acetyl-CoA:arylamine Nacetyltransferase, EC 2.3.1.5) after a variable lag period. Lengthening periods of exposure to light cause rapid increases in the sensitivity of pineal N-acetyltransferase to induction by isoproterenol. This supersensitivity, which develops gradually over a 12 hr period, is correlated with increasingly longer lag periods in the induction of the enzyme, and with progressively greater maximal response. Repeated administration of isoproterenol to supersensitive animals rapidly reverses the above changes and causes relative subsensitivity. The sensitivity of N-acetyltransferase to induction by dibutyryl-cyclic AMP added to pineals in organ culture was found to change in parallel with the sensitivity to isoproterenol. Stimulation of cyclic AMP levels in the pineal by isoproterenol was also greater in supersensitive rats than in the subsensitive animals, whether the supersensitivity had been caused by denervation or by exposure to light for 12 hr. The above experiments suggest that there are two sites for the regulation of the sensitivity of N-acetyltransferase to induction by catecholamines. The first site regulates the concentration of cyclic AMP achieved as a result of betaadrenergic stimulation. The second site regulates the capacity of intracellular processes (i.e., induction of Nacetyltransferase) to respond to cyclic AMP as a second messenger.The pineal hormone melatonin, as well as the enzymes and intermediates involved in its biosynthesis, exhibits marked circadian rhythms under the influence of environmental lighting (1-7). Thus, the highest levels of melatonin in the rat pineal occur during the night (1), in phase with the greatest activities of serotonin-N-acetyltransferase (arylamine acetyltransferase or acetyl-CoA: arylamine N-acetyltransferase, EC 2.3.1.5) (2). As the first specific enzyme in the branch pathway for melatonin synthesis (8), N-acetyltransferase is in a unique position to exert control over the activity of this pathway.N-Acetyltransferase activity (2, 9), and consequently melatonin synthesis (10), is controlled by a beta-adrenergic receptor mechanism. It appears likely that the circadian rhythms in N-acetyltransferase activity are generated by 24-hr rhythms in the turnover of noradrenaline (11) in the sympathetic terminals innervating the gland (12).The rate of firing of these postganglionic sympathetic fibers reflects changes in environmental lighting (13); electrophysiological stimulation of the preganglionic trunk to the superior Abbreviation: cyclic AMP, adenosine 3':5'-cyclic monophosphate. 1661 cervical ganglion elevates pineal N-acetyltransferase activity (14). The nocturnal increase in N-acetyltransferase activity is abolished by exposure of the animals to light, denervation by superior cervical ganglionectomy (9, 15), decentralization, or by treatment with reserpine, propranolol, or cycloheximide (9). These manipulation...

mentioning

confidence: 99%

Regulation of sensitivity to beta-adrenergic stimulation in induction of pineal N-acetyltransferase.

Romero¹,

Axelrod²

1975

“…Recent studies have shown that 3-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA), catecholamines, or monoamine oxidase inhibitors induce N-acetyltransferase activity in rat pineal organ in vivo that is blocked by prior treatment with a j8-adrenergic blocking agent (8). Electrical stimulation of the sympathetic nerve that innervates the rat pineal organ also causes an increase in N-acetyltransferase activity (9). These observations suggest that the neurotransmitter released from sym-2547 pathetic nerves regulates the activity of N-acetyltransferase in the pineal organ by stimulating the adrenergic ,-receptor and adenosine 3': 5'-cyclic monophosphate (cyclic AMP), and that the release of norepinephrine is modulated by environmental light and darkness.…”

mentioning

confidence: 99%

Control of Circadian Change of Serotonin N -Acetyltransferase Activity in the Pineal Organ by the β-Adrenergic Receptor

Deguchi

Axelrod

1972

259

Serotonin N-acetyltransferase (EC 2.3.1.5) activity in the rat pineal organ is enhanced 50-fold at night. Rats exposed to light at night or kept in darkness during the daytime do not show any elevation of enzyme activity.Treatment with reserpine, a compound that depletes norepinephrine from nerves, I-propranolol, a jB-adrenergic blocking agent, or cycloheximide, an inhibitor of protein synthesis, abolishes the nocturnal increase in serotonin Nacetyltransferase activity, indicating that the enzyme activity is modulated by neural release of norepinephrine from sympathetic nerves via jB-adrenergic receptors, and that the increase in enzyme activity is due to synthesis of new enzyme molecules. When rats are exposed to light at night or injected with I-propranolol, there is a precipitous fall in serotonin N-acetyltransferase activity (half-life 5 min). Cycloheximide administered at night results in a slow fall in enzyme activity (half-life 60 min). When rats are kept in darkness and then exposed to light for 10 mini, L-isoproterenol rapidly initiates the elevation of serotonin N-acetyltransferase activity to the initial level in 60 min. On the other hand, when the rats are kept in continuous light, L-isoproterenol initiates an increase in serotonin Nacetyltransferase activity after a lag phase of 60 min. The results indicate that there are two types of changes in serotonin N-acetyltransferase activity; a rapid increase and decrease mediated by the jl-adrenergic receptor, and a slow increase and decrease in enzyme activity that appears to represent the turnover of the enzyme.

“…The nocturnal rise was completely blocked by ganglionectomy or by decentralization of the superior cervical ganglion (3). Electrical stimulation of the sympathetic nerve that innervates the pineal organ resulted in a more than 3-fold elevation of N-acetyltransferase activity (4). N-Acetyltransferase activity increased in response to norepinephrine or dibutyryl adenosine 3': 5'-cyclic monophosphate in cultured rat pineal organ (5).…”

mentioning

confidence: 99%

Induction and Superinduction of Serotonin N -Acetyltransferase by Adrenergic Drugs and Denervation in Rat Pineal Organ

Deguchi

Axelrod

1972

151

Activity of serotonin N-acetyltransferase (EC 2.3.1.5) in rat pineal organ is rapidly and markedly elevated in vivo after administration of #-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA), norepinephrine, epinephrine, isoproterenol, monoamine oxidase inhibitors, or theophylline. Serotonin or 5-hydroxytryptophan has no effect on the increase in activity of this enzyme. Inhibitors of protein synthesis or propranolol, a jB-adrenergic blocking agent completely inhibit(s) the increase in activity of serotonin N-acetyltransferase induced by drugs, indicating that new enzyme molecules are formed via stimulation of ,-receptors of pineal cells and adenosine 3': 5'-cyclic monophosphate. When rat pineal organ is denervated by ganglionectomy, 8S-(3,4-dihydroxyphenyl)-L-alanine induces much more serotonin N-acetyltransferase than in the innervated gland. This superinduction by denervation appears to be due to changes of the postsynaptic site, probably the fl-adrenergic receptor on the pineal cell. Serotonin N-acetyltransferase (EC 2.3.1.5.) catalyzes the conversion of serotonin to N-acetylserotonin, the precursor of melatonin, a pineal hormone (1). N-Acetyltransferase activity in rat pineal organ has been shown to exhibit a circadian change with a 15-to 40-fold increase in the dark (2). The nocturnal rise was completely blocked by ganglionectomy or by decentralization of the superior cervical ganglion (3). Electrical stimulation of the sympathetic nerve that innervates the pineal organ resulted in a more than 3-fold elevation of N-acetyltransferase activity (4). N-Acetyltransferase activity increased in response to norepinephrine or dibutyryl adenosine 3': 5'-cyclic monophosphate in cultured rat pineal organ (5). It has also been demonstrated that formation of melatonin from tryptophan or serotonin was stimulated by norepinephrine (6) and blocked by propranolol (7) in a culture of rat pineal organ. These observations suggested that the concentration of N-acetyltransferase in rat pineal organ is regulated by norepinephrine released from adrenergic nerve endings by way of a ,-receptor and adenosine 3': 5'-cyclic monophosphate (cyclic AMP). There is, however, no conclusive evidence as to whether or not this mechanism is operating in the pineal organ in vivo.In this study, the effect of drugs on N-acetyltransferase activity was examined in rat pineal organs in vivo. We demonstrated that catecholamines, their precursor j%(3,4-dihydroxyphenyl)-iLalanine (iDOPA), inhibitors of monoamine oxidase (EC 1.4.3.4.), or theophylline cause a marked induction of pineal N-acetyltransferase that is blocked by propranolol or cycloheximide. In addition, a superinduction of N-acetyltransferase activity (100-fold increase) is observed with L-DOPA or inhibitors of monoamine oxidase in denervated rat pineal organ.