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Catecholamines and the Hydroxylation of Tyrosine in Synaptosomes Isolated from Rat Brain (DOPA/Tyramine/Dopamine/Norepinephrine/Octopamine) M

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Catecholamines and the Hydroxylation of Tyrosine in Synaptosomes Isolated from Rat Brain (DOPA/Tyramine/Dopamine/Norepinephrine/Octopamine) M Proc. Nat. Acad. Sci. USA Vol. 68, No. 10, pp. 2370-2373, October 1971 Catecholamines and the Hydroxylation of Tyrosine in Synaptosomes Isolated from Rat Brain (DOPA/tyramine/dopamine/norepinephrine/octopamine) M. KAROBATH Psychiatric Research Laboratories, Massachusetts General Hospital, Boston, Mass. 02114 Communicated by Seymour S. Kety, July 16, 1971 ABSTRACT Tyrosine hydroxylase activity of synapto- removing transmitters from an extraneuronal location at the somes isolated from rat brain was examined. A modified synapse, then incubation of synaptosomes with catechol- tritium-displacement assay was used, which allowed the measurement of tyrosine hydroxylase activity without the amines should inhibit the formation of DOPA from tyrosine. addition of either inhibitors of the metabolism of the The experiments demonstrate that tyrosine hydroxylase hydroxylated products or added exogenous cofactor. The activity is affected by catecholamine uptake. The concentra- enzyme activity was strongly inhibited by the addition of tions required to inhibit the synthesis of catechols are in the exogenous catecholamines and 3,4-dihydroxy-L-phenyl- M. alanine. Aromatic amines other than catechols did not range of 10-7 markedly influence tyrosine hydroxylase activity. These MATERIALS AND METHODS in vitro findings support the hypothesis that synthesis of catecholamines is regulated by a mechanism of end- [3,5-H]HifTyrosine (Tracerlab) was purified by column chro- product inhibition at the tyrosine hydroxylase step. matography. Catechol impurities were absorbed on alumina and tritiated water and anions were removed by Synaptosomes are pinched-off nerve endings with relatively columns (8), by non-neuronal elements (1, 2). They absorption on Dowex-50 resin. Tyrosine was eluted from little contamination Dowex-50 with 25 ml of 4 N HCl; after distillation of the eluate contain the enzymes necessary for the synthesis of dopamine (v/v) from tyrosine (3, 4). It has under reduced pressure, tyrosine was dissolved in 5% (3,4-dihydroxyphenethylamine) aqueous ethanol. This stock solution was stored at -70°C, not yet been demonstrated that nerve endings of brain contain use to re- that converts dopamine to norepinephrine. and aliquots were lyophilized immediately before the hydroxylase move spontaneously formed tritiated water. Ficoll was ob- Synaptosomes show tyrosine hydroxylase activity, even with- removed from the cofactor by this tained from Pharmacia and salt impurities were out the addition of pteridine required it by dialysis. enzyme (3). This finding suggests that nerve endings contain this cofactor and the reducing system used to regenerate it. Preparation of Synaptosomes. Male rats (170-190 g, Charles There is much evidence that tyrosine hydroxylase is normally River Breeding Co.) were decapitated. Brains were dissected the rate-limiting step in catecholamine biosynthesis (5). The free of the cerebellum, and homogenized in 0.32 M sucrose in a activity of the enzyme is thought to be regulated by end- glass Elvehjem-type homogenizer with a motor-driven Teflon product inhibition, so that dopamine and norepinephrine may pestle modified to provide 0.25-mm clearance (Kontes Glass regulate their own rates of synthesis by such a mechanism Co.). A crude mitochondrial fraction was prepared (14,000 X g (6, 7). While 3,4-dihydroxyphenylalanine (DOPA) also in- for 15 min, ref. 15), resuspended in isotonic sucrose, and layered hibits tyrosine hydroxylase in vitro (8), the lack of significant over discontinuous Ficoll density gradients (15). The gra- accumulation of DOPA in tissues normally (9) implies that dients were centrifuged in an SW 27 Spinco rotor at 27,000 rpm such a feedback mechanism is not likely to regulate DOPA syn- for 45 min (15). The nerve-ending fraction was removed thesis in vivo. The rate of neuronal catecholamine synthesis by aspiration, washed in isotonic sucrose to remove Ficoll, may be modulated by neuronal activity (10-13). This activity, and resuspended in the incubation medium. The total time of by releasing catecholamines at synapses, would lower intra- tissue preparation was 3 hr or less. All preparation were at neuronal catecholamine content and thus decrease the inhibi- 0-4°C. Electron microscopy showed the synaptosome fraction tion of synthesis. Such a system would provide for the re- to contain many structures identified as nerve-ending parti- plenishment of neurotransmitter substances as they are being cles, but membrane fragments were also present. inactivated. appears to be a major utilized and Reuptake of The method means of conserving transmitter catecholamines (14). The Determination Tyrosine Hydroxylase Activity. that could then inhibit further of Nagatsu et at. (16) was used with modifications. In this catecholamines reaccumulate amount amines be an assay, [3,5-3H]Ltyrosine is used as substrate, and the synthesis. Since active uptake of released may is the rate of catecholamine of tritiated water produced during the 3-hydroxylation important factor controlling syn- mM was undertaken to the measured. The incubation medium contained 100 NaCl, thesis, the present study investigate 5 2 mM Na of amines upon mM KCl, 10 mM. glucose, 50 mM sucrose, effects of accumulation exogenous tyrosine was buffered 15 mM in isolated nerve If reuptake of ascorbate, and 2 mM Na EDTA, and by hydroxylase activity endings. at was fresh daily. into terminals an role in Na phosphate pH 6.6. Ascorbate prepared amines presynaptic plays important The final tyrosine concentration was 1.5-2.5 X 10-6 M, with Abbreviation: DOPA, 3,4-dihydroxyphenylalanine. about 1 MCi of [3H]tyrosine present in each tube. The total 2370 Downloaded by guest on September 23, 2021 Proc. Nat. Acad. Sci. USA 68 (1971) Tyrosine Hydroxylation in Synaptosomes 2371 incubation volume was 0.5 ml. Samples were incubated in a aration, the tyrosine hydroxylase assay gave precise results of metabolic shaker-bath at 37°C for 30 min. The reaction was 3.06 + 0.21 (SD) pmol per min per mg of protein (N = 9). stopped by addition of 0.05 ml of 2 M Na acetate buffer (pH Tyrosine hydroxylase in intact synaptosomes incubated 4.5) and the tubes were cooled on ice. After low-speed centrif- as in these experiments was found to be half-saturated by a ugation at 0°C, supernatants were transferred quantitatively substrate concentration in the medium of about 3 X 10- M to a small column of Dowex 50 X 8 resin (200-400 mesh, tyrosine. With a concentration of tyrosine (2 X 10-5 M) H+-form, 0.4 X 2 cm), which was placed on a column of found to be saturating and used in the present experiments, Dowex 1 X 8 resin (200-400 mesh, OH--form, 0.4 X 2 cm). incubation with various amounts of synaptosomes showed Columns were then washed three times with 0.85-ml portions that the assay was linear with tissue concentrations from 0.12 of water. Aliquots (2 ml) of the combined effluents were trans- to 0.90 mg of protein per assay tube. The optimum pH for ferred to counting vials, mixed with 13 ml of Bray's solution tyrosine hydroxylase was found to be between 6.0 and 6.7. (17), and counted in a Packard scintillation counter. In order In the present experiments, the reactions were performed at to estimate contaminating neutral metabolites, the remain- pH 6.6 and contained 0.3-0.8 mg of synaptosomal protein per ing effluent material was lyophilized to dryness; the residue assay tube. In confirmation of previous findings (8, 22), 3- was taken up in 1.0 ml of water and counted in 7 ml of Bray's iodotyrosine and a-methyl-p-tyrosine were found to be very solution. Incubation of [3H]tyrosine, either with tissue at strong inhibitors of tyrosine hydroxylase at 10-4 M (Table 1). 0-40C or without tissue at 37°C, permitted estimations of This assay method allows the-measurement of tyrosine hy- the amount of spontaneously formed radioactive water. Both droxylase activity in synaptosomes without interfering with methods indicated that less than 0.1% of the total tritium the further metabolism of the newly synthesized DOPA. present in the incubation mixture was released nonenzymati- The assay was used to study the effect of various compounds cally. Counting efficiency was determined by the internal- on synaptosomal tyrosine hydroxylase activity. The synapto- standard method (18). somes were incubated under conditions known to permit the uptake of exogenous catecholamines (23, 24), and near the op- Estimation of Tyrosine Accumulation by Synaptosomes. A timum pH for tyrosine hydroxylase activity. Since the incuba- Millipore filter technique was used (19). Aliquots of 0.2 ml with were removed from the incubation mixture, pipetted into 5 ml tion mixture was not fortified the pteridine cofactor, tyrosine hydroxylase activity was dependent on the endoge- of ice-cold 0.32 M sucrose, and poured on a moistened 25-mm nous cofactor and its regenerating system. Ascorbic acid and Millipore filter (0.65-,um pore-size), which was washed oxidation of twice with 10-ml portions of 0.32 M sucrose. The filter was EDTA were added to prevent nonenzymatic then dried under an infrared lamp and placed in a counting catecholamines. vial with 10 ml of a toluene solution containing 2,5-diphenyl- In the present experiments, it was found that exogenous oxazole (0.4%) and p-bis- [2-(4-methyl-5-phenyloxazolyl)] ben- norepinephrine, dopamine, or DOPA, in concentrations as low zene (0.01%) (Packard Instrument Co.). as 10-7 M, can inhibit tyrosine hydroxylation (Table 2). Up- take of exogenous amines raises the intrasynaptosomal con- Miscellaneous Procedures. Tyrosine was measured by the centration of the inhibitory amines to concentrations con- fluorometric method of Waalkes et al. (20) after elution from siderably higher than those in the incubation medium (14). Dowex-50 chromatography columns with 1 N NH40H, which The Km values for catecholamine uptake by synaptosomes in was removed by distillation under reduced pressure.
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