Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The carrier molecule that transports dopamine (DA) across the synaptic membrane is known as the dopamine transporter (DAT). Depending on the ionic conditions, DAT may function as a mediator of both the inward directed DA transport known as the "reuptake" and the outward directed DA transport known as the "release." The functional significance of DAT is in the regulation of DA neurotransmission by terminating the action of DA in the synapse via reuptake. With use of DAT binding as a presynaptic marker to measure altered DA innervation, abnormalities of the DAT binding have been demonstrated in idiopathic Parkinson's disease, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity, and progressive supranuclear palsy. Moreover, the identification of DAT as the neuronal element that mediates the addictive properties of cocaine highlights its significance in cocaine addiction. Cocaine binding in the brain is heterogeneous, and there is an uneven distribution of the high- and low-affinity binding sites across the anatomical regions. Regional differences in ligand binding are observed by using both [3H]cocaine and the diphenyl-substituted piperazine derivatives known as the "GBR series" of ligands. The identification of compounds that inhibit the binding of medications for cocaine abuse. Furthermore, clarification of the various binding domains that may be relevant to transporter function in human neuropsychiatric disorders may lead to the development of new medications for schizophrenia, Tourette's disease, and drug addiction.
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PMID:Molecular, functional and biochemical characteristics of the dopamine transporter: regional differences and clinical relevance. 814 55

Dopamine transporter messenger RNA (mRNA) expression was assessed by in situ hybridization over individual pigmented neurons from the substantia nigra pars compacta in midbrain sections from 7 parkinsonian and 7 age-matched, neurologically normal patients. In the normal control brains, high levels of expression of dopamine transporter mRNA were noted over pigmented neurons in the substantia nigra pars compacta; neurons in the adjacent nucleus paranigralis of the ventral tegmental area displayed less hybridization. Nigra compacta neurons surviving in brains of patients with Parkinson's disease displayed only 57% of the dopamine transporter mRNA hybridization intensity displayed by nigral neurons in normal control brains. The disease-related decrease in the apparent level of dopamine transporter mRNA expression in remaining neurons could reflect neuronal dysfunction. Conceivably, it might also reflect differential vulnerability of those neurons that initially expressed higher levels of this transporter to the insult of parkinsonism.
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PMID:Dopamine transporter messenger RNA in Parkinson's disease and control substantia nigra neurons. 815 80

The iodinated cocaine analogue 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT), a new dopamine transporter, was preliminary tested in human brain. Two normal volunteers and two patients with Parkinson's disease were imaged with a high-resolution single-photon emission tomography scanner. The specific binding of [123I]beta-CIT in the basal ganglia and thalamus was high in normal volunteers. In addition, there was relatively intense uptake in the medial prefrontal area. Patients with Parkinson's disease who were older than controls showed significantly lower specific binding in the basal ganglia and thalamus and no uptake in the medial prefrontal cortex. This decrease in the dopamine transporter may be age related.
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PMID:Initial experience with single-photon emission tomography using iodine-123-labelled 2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane in human brain. 822 73

MPP+ (1-methyl-4-phenylpyridinium), a dopaminergic neurotoxin that provides the best available experimental model of Parkinson's disease, is selectively concentrated in dopamine neurons by the dopamine transporter (DAT). DAT also serves as a primary recognition site for cocaine. To help define selective molecular mechanisms by which MPP+ uptake occurs, we have tested dopamine transporters mutated in several residues for their abilities to accumulate dopamine and MPP+, and to bind a cocaine analog. Mutants in DAT 7th and 11th hydrophobic putative transmembrane domains increase MPP+ uptake velocity and affinity (1/KD), respectively. These mutations exert much more modest effects on dopamine uptake and have little impact on cocaine analog binding. These findings provide the first example of mutations that enhance transport and identify specific DAT amino acids selectively involved in neurotoxin uptake. They may also have implications for the feasibility of developing drugs that could specifically block accumulation of Parkinsonism-inducing neurotoxins.
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PMID:Dopamine transporter mutants selectively enhance MPP+ transport. 831 Apr 26

Parkinson's Disease (PD) is characterized by a selective loss of nigrostriatal dopaminergic neurons that results in a marked reduction of dopaminergic nerve terminals in the striatum. Recently, 11C-WIN 35,428, a cocaine analogue that specifically labels the dopamine transporter, was developed and can be used to label dopaminergic nerve terminals in vivo by positron emission tomography. In healthy control subjects, binding of 11C-WIN 35,428 is highest in the striatum. In addition, 2 symmetrical focal areas of low binding were observed in the midbrain. The cerebellum functioned as an appropriate region for nonspecific binding. The binding of 11C-WIN 35,428 in patients with PD (Hoehn-Yahr II) was compared with that in healthy control subjects by using the (region-cerebellum)/cerebellum ratio for data acquired 34 to 82 minutes after injection. In control subjects, this ratio varied, at approximately 2, in the striatum. In patients with PD, binding in the posterior putamen was reduced by 78%, whereas the anterior putamen and the caudate nucleus showed a reduction of 59 and 39%, respectively. The reduction in 11C-WIN 35,428 binding was highest in the midbrain (84%). The high specific/nonspecific binding ratio and the pronounced reduction in binding in mild PD may permit detection of even earlier stages of PD or presymptomatic individuals with dopaminergic cell loss.
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PMID:Positron emission tomographic imaging of the dopamine transporter with 11C-WIN 35,428 reveals marked declines in mild Parkinson's disease. 812 97

Nigrostriatal dopaminergic neurons play an essential role in the central regulation of motor functions. These functions are initiated through the release of dopamine from axon terminals in the striatum or from dendrites in the substantia nigra (SN) and are terminated by the reuptake of dopamine by the sodium- and chloride-dependent dopamine transporter (DAT). DAT also can transport dopamine neurotoxins and has been implicated in the selective vulnerability of nigrostriatal dopaminergic neurons in major models of Parkinson's disease. We have used electron microscopic immunocytochemistry with an N-terminal domain anti-peptide antibody to examine the subcellular distribution of DAT in the rat SN and dorsolateral striatum. In the SN, immunogold labeling for DAT was localized to cytoplasmic surfaces of plasma membranes and smooth endoplasmic reticulum of dendrites and dendritic spines, few of which contained synaptic vesicles. Neuronal perikarya in the SN contained immunogold-labeled pleomorphic electron-lucent tubulovesicles but showed immunolabeling of plasma membranes only rarely. Axon terminals in the striatum contained extensive immunogold labeling of cytoplasmic surfaces of plasma membranes near aggregates of synaptic vesicles and less frequent labeling of intervaricose segments of plasma membrane or small electron-lucent vesicles. In sections dually labeled for DAT and the catecholamine-synthesizing enzyme tyrosine hydroxylase, both markers were colocalized in most profiles in the SN and striatum. These findings support the proposed topological model for DAT and suggest that this transporter is strategically located to facilitate uptake of dopamine and neurotoxins into distal dendritic and axonal processes of nigrostriatal dopaminergic neurons.
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PMID:The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons. 855 28

We have used in vivo single-photon emission computed tomography (SPECT) of the dopamine transporter with 2 beta-carboxymethoxy-3 beta-(4-iodophenyl)tropane ([123I] beta-CIT) to investigate striatal dopamine transporter loss in patients with early Parkinson's disease (PD). Striatal uptake of ([123I] beta-CIT was compared in eight early-PD patients with exclusively hemi-parkinsonism and eight age- and sex-matched healthy subjects. [123I] beta-CIT striatal uptake was reduced by approximately 53% contralateral and by 38% ipsilateral to the clinically symptomatic side in the hemi-PD patients, compared with the mean striatal uptake in age- and sex-matched healthy subjects. The relative reduction in [123I] beta-CIT uptake in the hemi-PD patients was greater in the putamen than in the caudate. These data demonstrate that SPECT imaging of the dopamine transporter with [123I] beta-CIT can identify patients with PD at the onset of motor symptoms and suggest that this technique also may be useful in identifying individuals with developing dopaminergic pathology before onset of motor symptoms.
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PMID:[123I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson's disease. 855 82

Methamphetamine is a drug that is significantly abused worldwide, Although long-lasting depletion of dopamine and other dopamine nerve terminal markers has been reported in striatum of nonhuman primates receiving very high doses of the psychostimulant, no information is available for humans. We found reduced levels of three dopamine nerve terminal markers (dopamine, tyrosine hydroxylase and the dopamine transporter) in post-mortem striatum (nucleus accumbens, caudate, putamen) of chronic methamphetamine users. However, levels of DOPA decarboxylase and the vesicular monoamine transporter, known to be reduced in Parkinson's disease, were normal. This suggests that chronic exposure to methamphetamine does not cause permanent degeneration of striatal dopamine nerve terminals at the doses used by the young subjects in our study. However, the dopamine reduction might explain some of the dysphoric effects of the drug, whereas the decreased dopamine transporter could provide the basis for dose escalation occurring in some methamphetamine users.
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PMID:Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. 864 May 65

The uptake and cytotoxicity of 1-methyl-4-phenylpyridinium (MPP+), the toxic metabolite of the parkinsonism inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), were studied in COS-7 cells transiently transfected with the cloned human noradrenaline and dopamine transporters and in permanently transfected SK-N-MC neuroblastoma cells. MPP+ had a 10- to 20-fold lower K(m) value for the noradrenaline than for the dopamine transporter. In dopamine transporter expressing cells, the maximal transport rate (Vmax) of MPP+, dopamine and noradrenaline was the same, but in noradrenaline transporter expressing cells the Vmax of MPP+ and dopamine was only one-half of the Vmax of noradrenaline. The turnover numbers (Vmax of uptake/maximal binding sites of binding) were 5 times higher for the dopamine transporter (as measured with [3H]dopamine and [3H]-2 beta-carbomethoxy-3 beta-(4-fluorophenyl) tropane than for the noradrenaline transporter (as measured with [3H]noradrenaline and [3H]nisoxetine). In SK-N-MC cells with similar Vmax values for both catecholamines, noradrenaline transporter expressing cells were killed by lower concentrations of MPP+ in the medium than dopamine transporter expressing cells. Desipramine blocked the toxicity of MPP+ toward the noradrenaline transporter, but not the dopamine transporter expressing cells. We conclude that the toxic effect of MPTP at the striatal dopamine system in the MPTP primate model of Parkinson's disease is not correlated with the affinity profile of MPP+ for catecholamine transporters, but rather with the higher turnover number of MPP+ at the dopamine transporter. In contradistinction, the toxicity of MPTP at the noradrenaline neurons in the primate cerebral cortex (Pifl et al., 1991) may involve the higher affinity of MPP+ for the noradrenaline transporter.
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PMID:Catecholamine transporters and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity: studies comparing the cloned human noradrenaline and human dopamine transporter. 866 8

The dopamine transporter (DAT) is the carrier protein that transports dopamine across the presynaptic membrane. The DAT terminates the action of dopamine (DA) in the synapse via reuptake and thus regulates DA neurotransmission. The transporter has been studied by direct binding techniques using a variety of ligands which are inhibitors of DA transport. DAT binding, both in vivo (positron emission tomography) and in vitro (post mortem) may serve as a presynaptic marker to measure altered DA innervation in several neuropsychiatric diseases such as idiopathic Parkinson's disease, Tourette's disease, schizophrenia or cocaine addiction. In Parkinson's disease, a reduction in the density of binding sites could be due either to a degeneration of the terminal dopaminergic projections or to a compensatory readjustment in the level of dopamine synaptic transmission. This dopaminergic cell specific marker could also aid in attempts to elucidate the rate at which dopaminergic cells are lost in this disease. MPTP (a neurotoxin which induces a parkinsonian-like syndrome after conversion in MPP+) uses DAT to enter the neuron and exert its toxic effect which may be prevented by pretreatment with DA uptake blockers. In cocaine abuse, DAT mediates the addictive properties of cocaine. Cocaine binding sites on the carrier may be distinct from DA binding sites allowing the development of medication sparing the DA function but impairing the cocaine effects. In schizophrenia, functional DA uptake was reported to be increased in the striatum in post mortem brains, whereas the kinetic parameters of the uptake sites were unchanged using different transporter labeling ligands. Thus, this marker does not provide any evidence for the dopaminergic hypothesis, but an impairment of the DAT itself could possibly be involved in the etiology of schizophrenia. However, the possible interaction of drugs such as L-Dopa or neuroleptic treatment with transporter binding may be taken into account in the results analysis. Finally, the DAT gene is also an important candidate gene for psychiatric diseases such as schizophrenia or cocaine abuse.
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PMID:[The dopamine transporter: characterization and physiopathologic implications]. 867 69


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