Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuronal dopamine transporter/uptake site can be covalently labeled with the photoaffinity probe 1-(2-[bis-(4-fluorophenyl) methoxy]ethyl)-4-[2-(4-azido-3-[125I]iodophenyl)ethyl]piperazine [( 125I]FAPP) and visualized following sodium dodecyl sulfate polyacrylamide gel electrophoresis and autoradiography. Upon photolysis, [125I]FAPP specifically incorporated into a polypeptide of apparent Mr = 62,000 in membranes from both the putamen and the caudate nucleus of control, Alzheimer's, schizophrenia, and Huntington's diseased brain, and following complete deglycosylation, migrated as an Mr approximately 48,000 polypeptide. In parkinsonian postmortem putamen, however, there was no detectable photoincorporation of [125I]FAPP into the ligand binding subunit of the dopamine transporter. [125I]FAPP did specifically label the Mr 62,000 polypeptide of parkinsonian caudate, although with efficiencies of 20-50% of control. The asymmetrical loss of the dopamine transporter in Parkinson's diseased striatum was confirmed in reversible receptor binding experiments using [3H]GBR-12935 (3H-labeled 1-[2-(diphenylmethoxy) ethyl]-4-(3-phenylpropyl)piperazine). In parkinsonian putamen, mazindol competitively inhibited the binding of [3H]GBR-12935 with an estimated affinity (Ki approximately 2,000 nM) 10 times lower than in controls (Ki approximately 30 nM), while the affinity of maxindol for [3H]GBR-12935 binding in the caudate was equal to that seen with controls (Ki approximately 50 nM). The proportion of [3H]GBR-12935 binding sites recognized by mazindol with high affinity in Parkinson's diseased caudate was, however, reduced by 50-80%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The dopamine transporter is absent in parkinsonian putamen and reduced in the caudate nucleus. 198 18

To investigate changes in the relation between presynaptic and postsynaptic dopaminergic functions in vivo in both nigrostriatal and mesocortical systems in Parkinson's disease (PD), 10 drug-naive early PD patients were studied twice using positron emission tomography with [11C]CFT (dopamine transporter probe) followed by [11C]SCH 23390 (D1 receptor probe). Regional binding potentials (k3/k4) of [11C]CFT and [11C]SCH 23390 in the striatum (nigrostriatal system) and the orbitofrontal cortex (mesocortical system) were estimated by compartment analyses. Levels of [11C]CFT k3/k4 in the two projection areas were shown to be significantly lower in PD, whereas [11C]SCH 23390 levels remained unchanged. Regression analysis showed that estimates of CFT k3/k4 were positively correlated with those of SCH 23390 k3/k4 in the striatum in normal control, whereas the two binding estimates were less positively correlated in the caudate and inversely correlated in the putamen in PD. No significant correlation was observed in the orbitofrontal cortex in both groups. These results indicated that dopamine transporters and D1 receptors change in parallel in the normal striatal synapses, but the association becomes asymmetrical because of reduction in presynaptic and relative elevation in postsynaptic markers in PD. Alterations in synaptic parallel regulation in the nigrostriatal system might reflect early pathophysiology in the parkinsonian brain.
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PMID:Presynaptic and postsynaptic dopaminergic binding densities in the nigrostriatal and mesocortical systems in early Parkinson's disease: a double-tracer positron emission tomography study. 1055 89

The plasma membrane dopamine transporter is located on presynaptic nerve terminals and is responsible for the termination of dopaminergic neurotransmission via dopamine reuptake. The dopamine transporter may also contribute to the pathogenesis of Parkinson disease. Dopamine transporter expression correlates well with susceptibility to neuronal degeneration in 1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine (MPTP)-induced parkinsonism. Recent studies have implicated the dopamine transporter in the uptake of both this neurotoxin and its metabolite, MPP(+), as well as another experimental neurotoxin, 6-hydroxydopamine. In these studies we examined the role of the dopamine transporter in the neurotoxicity of both MPP(+) and 6-hydroxydopamine in the rat brain using in vivo administration of phosphorothioate antisense oligonucleotides targeting dopamine transporter mRNA. Infusion of dopamine transporter antisense (1 nmol/day, 7 days) into the left substantia nigra pars compacta resulted in reduced (3)H-WIN 35-428 binding in the left striatum and significant levodopa and amphetamine-induced contralateral rotations. Unilateral pretreatment with dopamine transporter antisense prior to bilateral intrastriatal infusion of either MPP(+) or 6-hydroxydopamine resulted in asymmetrical striatal (3)H-WIN 35-428 binding and dopamine content as well as significant apomorphine-induced ipsilateral rotations, suggesting neuroprotection of nigrostriatal neurons on the antisense-treated side. Thus, the dopamine transporter appears to play a critical role in determining susceptibility to the experimental neurotoxins MPP(+) and 6-hydroxydopamine. In light of this, the dopamine transporter may prove useful, both as a marker for susceptibility to Parkinson's disease and as a target for therapeutic intervention.
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PMID:Dopamine transporter function assessed by antisense knockdown in the rat: protection from dopamine neurotoxicity. 1088 Oct 39