A Mutation Influencing the Transportation of Manganese, L-Dopa, and L-Tryptophan

Cotzias, George C.; Tang, Lei-Han; Miller, Samuel T.; Sladic-Simic, D.; Hurley, Lucille S.

doi:10.1126/science.176.4033.410

Cited by 50 publications

(25 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to these sex-or drug-linked differences in the intensity of the neurological reactions of mice to levodopa, we had demonstrated earlier some genetically determined differences-for example, in the manganese mouse mutant pallid (papa) versus its C57 BL/6J (PaPa) control (11). Genetically determined differences were also found here.…”

Section: Discussionmentioning

confidence: 48%

“…We had found earlier that the intensity of neurological responses evoked by standard single doses of levodopa in mice was sex-dependent (10) and was influenced by some genetic factors (11) and some pharmacological pretreatments (12,13). One could therefore select appropriate groups so that the reactions of the mice in each group to single injections of levodopa would differ from those of the other groups (11)(12)(13).…”

mentioning

confidence: 99%

“…One could therefore select appropriate groups so that the reactions of the mice in each group to single injections of levodopa would differ from those of the other groups (11)(12)(13). One thereafter, in corresponding mice, the degree by which standard concentrations of dopamine activate the adenylate cyclases in homogenates of the caudate.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Quantitative correlation of dopamine-dependent adenylate cyclase with responses to levodopa in various mice.

Tang¹,

Cotzias²

1977

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We obtained 12 groups of mice with widely different neurological responses to levodopa by selecting them from different strains and submitting some of them to pretreatments. We scored the symptoms evoked by a standardized dose of levodopa in one subgroup from each group. We tested another subgroup for activation of an adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] by a standardized dose of dopamine added to homogenates of the caudate nuclei of the brains of these mice. Both sets of tests were performed randomly. When the accruing two sets of data were plotted against each other there emerged a straight line which fitted the data with a coefficient of correlation of 0.97 (P < 0.0001). The dopamine-dependent activity of the adenylate cyclase of the brain was thus shown to be a determinant of the neurological responses of intact animals to a dopaminergic drug.Greengard and his colleagues discovered a dopamnine-activated adenylate cyclase in homogenates of caudate nuclei (1-3) which appears to be the site of interaction between dopamine and the receptors on the membranes of postsynaptic dopaminergic neurons. The enzyme synthesizes a second messenger, adenosine 3':5'-cyclic monophosphate (cyclic AMP), governing the neuron's response to dopamine.-This enzyme seems to play a behavioral role in animals and man since neuroactive drugs tested against the adenylate cyclase have imitated drug effects seen in animals or man. The dopamine-dependent activity, for example, was selectively inhibited by antipsychosis drugs that block the mental effects of dopamine (4)(5)(6)(7)(8). These drugs, however, can induce pharmacological parkinsonism. Dopaminergic drugs in low concentrations potentiated selectively the enzyme's dopaminedependent activity but higher concentrations caused inhibition (2, 9). Furthermore, mutually antagonistic drugs, the cholinergic and anticholinergic ones, both-inhibited this enzyme (9). The sum of this evidence was only suggestive but did not prove a behavioral function of this enzymatic activity (9). It was useful, therefore, to seek quantitative correlations between (i) selected neurological or behavioral scores in intact animals and (ii) the dopamine-dependent activity of the cyclase in homogenates of brains from corresponding animals. Such a correlation would strengthen the assumption of a behavioral role without precluding a search for further functions (9).We had found earlier that the intensity of neurological responses evoked by standard single doses of levodopa in mice was sex-dependent (10) and was influenced by some genetic factors (11) and some pharmacological pretreatments (12, 13). One could therefore select appropriate groups so that the reactions of the mice in each group to single injections of levodopa would differ from those of the other groups (11-13). One could test Abbreviations: cyclic AMP, adenosine 3':5'-cycic monophosphate; HS, Hale-Stoner strain of Swiss albino mice.

show abstract

Section: Discussionmentioning

confidence: 48%

mentioning

confidence: 99%

See 1 more Smart Citation

Quantitative correlation of dopamine-dependent adenylate cyclase with responses to levodopa in various mice.

Tang¹,

Cotzias²

1977

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…3) and the development of a genetic mutant in mice known as the "pallid mouse" in the offspring of manganese deficient animals (ref. 4). Both these problems can be completely prevented by diets supplemented with manganese.…”

Section: Introductionmentioning

confidence: 99%

Determination of manganese in biological materials

Ottaway¹,

Halls²

1986

Pure and Applied Chemistry

View full text Add to dashboard Cite

show abstract

“…The opposite suggestion might, however, emerge from the following. Nicotinamide, an inhibitor of tRNA transmethylase (12), has blocked the cerebral effects of -dopa (13), while such effects were minimal in the mouse mutant pallid, in which cerebral uptake of large neutral amino acids was slow (14). It was, thus, interesting to determine whether any of these suggestions was germane.…”

mentioning

confidence: 99%

Changing the Actions of Neuroactive Drugs by Changing Brain Protein Synthesis

Tang¹,

Cotzias²,

Dunn³

1974

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Diminution of cerebral protein synthesis diminished the cerebral responses of mice to some neuroactive drugs, while an increase in synthesis increased the responses. Protein synthesis in whole brains (tested in vitro ) was diminished by giving living mice different inhibitors by different routes. The inhibitors tested (chloramphenicol, cycloheximide, and puromycin) diminished the behavioral responses of the mice to levodopa without affecting either its cerebral uptake or its conversion to dopamine. A diminution of the reactions of dopaminergic receptors was suggested by the diminished responses to the dopaminergic drug, apomorphine, while participation of cholinergic ones was suggested by experiments with oxotremorine. Proof that receptors had been specifically involved was secured on homogenized caudate nuclei from chloramphenicol-treated mice, in which the dopamine-activated production of cyclic AMP was markedly diminished. A stimulator of cerebral protein synthesis, the artificial double-stranded RNA, poly(I)·poly(C), increased the behavioral responses to these three drugs while it increased the dopamine-activated production of cyclic AMP. Since all these experimental increases or decreases in the responses to drugs required the lapse of only a few hours, proteins with rapid turnover rates must be critical in the activation of several kinds of cerebral receptors.

show abstract

A Mutation Influencing the Transportation of Manganese, L-Dopa, and L-Tryptophan

Abstract: Transportation of manganese, L-dopa, and L-tryptophan was slower through the tissues, of intact pallid mice than through those of black C57Bl/6J mice, presumably because of the influence of the gene pallid.

Cited by 50 publications

References 16 publications

Quantitative correlation of dopamine-dependent adenylate cyclase with responses to levodopa in various mice.

Quantitative correlation of dopamine-dependent adenylate cyclase with responses to levodopa in various mice.

Determination of manganese in biological materials

Changing the Actions of Neuroactive Drugs by Changing Brain Protein Synthesis

Contact Info

Product

Resources

About