Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The introduction of D1A dopamine receptors and mu-opioid receptors into HEK 293 cells that were also transiently transfected with adenylyl cyclase cDNA imparted to dopamine and to mu-opioid receptor agonists the ability to modulate the activity of the expressed adenylyl cyclase. Dopamine added to cells expressing D1A receptors and type V adenylyl cyclase significantly stimulated type V enzyme activity. The concomitant addition of morphine produced a dose-dependent inhibition of dopamine-stimulated type V adenylyl cyclase activity. On the other hand, if the HEK 293 cells were transfected with cDNA for type VII adenylyl cyclase instead of the type V isoform, morphine stimulated this adenylyl cyclase activity beyond the stimulation produced by dopamine. Both the inhibitory and stimulatory effects of morphine were blocked by naloxone or pretreatment of the transfected HEK 293 cells with pertussis toxin. When expressed in the HEK 293 cells, the alpha subunit of transducin, which is considered to be the putative scavenger of the beta gamma subunits of G proteins, suppressed the stimulatory effect of morphine on type VII adenylyl cyclase. We also expressed the adenylyl cyclases in cells that were transfected with D1A receptor and G beta 1 and G gamma 2 cDNAs. Dopamine was more efficacious in stimulating type VII adenylyl cyclase activity in cells concomitantly transfected with the beta gamma subunit cDNAs than in cells not transfected with these G protein subunits. Transfection with beta gamma subunit cDNAs did not affect dopamine stimulation of type V adenylyl cyclase activity, and morphine-induced inhibition of type V adenylyl cyclase activity was still evident in cells cotransfected with the alpha subunit of transducin. These data support the contention that the effects on type VII adenylyl cyclase activity mediated through the G1/G(o) proteins may depend on the actions of the beta gamma subunits. The same is not the case for type V adenylyl cyclase. Our data demonstrate that both qualitative and quantitative responses to mu-opioid receptor stimulation depend on the isoform of adenylyl cyclase expressed in neurons or other cells of the body.
Mol Pharmacol 1996 Jul
PMID:mu-Opioid receptors inhibit dopamine-stimulated activity of type V adenylyl cyclase but enhance dopamine-stimulated activity of type VII adenylyl cyclase. 870 Jan 17

We examined the phenotypic changes of neuroblastoma cells chronically treated with cAMP and nanomolar concentrations of staurosporine. These agents, given together, produced cells with a neuronal morphology and a delayed increase (approximately 10 days) in synapsin I mRNA levels. Dopamine-beta hydroxylase mRNA was upregulated within 24 h. We provide evidence that low-dose staurosporine acts cooperatively with cyclic AMP in the acquisition of mature neuronal phenotypes.
Brain Res Mol Brain Res 1996 Aug
PMID:Long-term regulation of synapsin I gene expression and neuronal morphology by cyclic AMP and low-dose staurosporine. 884 26

Dopamine produces a time- and dose-dependent increase in cell death in a clonal catecholaminergic cell line (CATH.a) derived from the central nervous system. Cell death also occurred after treatment with the catecholamines L-dihydroxyphenylalanine, norepinephrine, epinephrine, and isoproterenol, as well as the neurotoxic compound 6-hydroxydopamine. Cell death is not receptor mediated because selective noradrenergic and dopaminergic receptor agonists had no effect on CATH.a cell viability. Dopamine induces apoptotic cell death as indicated by DNA fragmentation measured by gel electrophoresis and by flow cytometric analysis. Apoptosis seems to be produced by dopamine autoxidation, because intracellular peroxides increase after dopamine treatment and cell death can be inhibited by catalase and N-acetylcysteine. N-acetylcysteine produced a dose-dependent decrease in dopamine-induced cell death; this correlated with a decrease in peroxide formation. In addition, antisense to the antioxidant protein bcl-2 increases the sensitivity of CATH.a cells to dopamine-induced cell death. These findings indicate that the oxidative products of dopamine cause neurotoxicity through apoptosis.
Mol Pharmacol 1996 Nov
PMID:Dopamine induces apoptotic cell death of a catecholaminergic cell line derived from the central nervous system. 891 62

Dopamine-induced DNA damage was studied in vitro in the presence of the enzyme tyrosinase. Dopamine auto-oxidizes to form dopamine quinone, a reactive molecule which spontaneously decomposes to form additional reactive species that can modify cellular macromolecules. The conversion of dopamine to reactive dopamine quinone is accelerated by the enzyme tyrosinase. The objective of this study was to evaluate whether dopamine autoxidation would lead to DNA-reactive intermediates and whether tyrosinase would increase the rate of this reaction. Incubation of DNA with [3H]dopamine resulted in the concentration-dependent covalent incorporation of the labeled catecholamine into precipitable nucleic acid (DNA adduct formation). The presence of tyrosinase increased the incorporation by as much as two orders of magnitude. Antioxidants markedly reduced this incorporation, suggesting that dopamine free-radicals were critical in DNA modification. DNA adducts formed by dopamine in the presence of tyrosinase were visualized using 32P-postlabeling and thin layer chromatography. The results suggest that DNA modification by dopamine is accelerated by tyrosinase which, in turn, could contribute to destruction of dopaminergic neurons in vivo.
Brain Res Mol Brain Res 1996 Nov
PMID:Tyrosinase enhances the covalent modification of DNA by dopamine. 891 97

1. An identified dopaminergic interneuron (RPeD1) of the snail Lymnaea stagnalis, makes specific synaptic connections with a number of target (VI and VJ) but not non-target (VF and RPB) neurons in vivo. When cultured in vitro with both target and non-target cells, RPeD1 re-establishes synapses with target cells only. 2. To test whether exogenous dopamine exerts effects on the neurite outgrowth of both target and non-target neurons respectively, these cells were cultured in conditioned media (CM) in the presence of dopamine (10(-5) M). The growth of the non-target cells was severely restricted and retarded in the presence of dopamine. These data suggest that dopamine may regulate neurite outgrowth of non-target cells in culture. 3. The growth regulatory effects of dopamine on the non-target cells were blocked in the presence of a dopamine receptor antagonist (R(+) SCH-23390, 10(-4) M). These results indicate that dopamine-induced growth regulation of the non-target cells is mediated via dopamine receptors on these cells. 4. In the absence of conditioned media, dopamine was not sufficient to exert growth promoting effects on either target or non-target cells. 5. Taken together, our data show that dopamine differentially regulates growth of identified Lymnaea neurons in culture. Dopamine alone, however, is not sufficient to initiate and support neurite outgrowth from these cells. Rather, it functions to suppress the neurite outgrowth of the non-target cells, initiated by the conditioned media.
Cell Mol Neurobiol 1996 Oct
PMID:Dopamine regulation of neurite outgrowth from identified Lymnaea neurons in culture. 895 10

We identified a novel azaindole derivative, L-750,667, that has high affinity (Ki = 0.51 nM) and >2000-fold selectivity for D4 dopamine receptors compared with its activity at D2 and D3 dopamine receptors. L-750,667 had little affinity for rat D1/D5 dopamine receptors, sigma binding sites, or 5-hydroxytryptamine1A or 5-hydroxytryptamine2 receptors. In functional studies, L-750,667 exhibited high affinity antagonist activity at D4 receptors, reversing dopamine (1 microM)-induced inhibition of cAMP accumulation in human embryonic kidney (HEK) cells expressing the human D4 receptor (hD4 HEK) with an EC50 value of 80 nM. The radioiodinated form of L-750,667 bound specifically to the human dopamine D4 receptor expressed in HEK cells and saturation analysis revealed a single high affinity binding site for [125I]L-750,667 (Kd = 0.16 +/- 0.06 nM). The maximum number of binding sites (Bmax) estimated using [125I]L-750,667 in hD4 HEK cells was 251 +/- 71 fmol/mg, which correlated well with the Bmax value determined using [3H]spiperone (227 +/- 83 fmol/mg) in the same membrane preparations. The pharmacological profile of [125I]L-750,667 binding to hD4 HEK cells was evaluated using known dopamine receptor agonists and antagonists. The rank order of potencies for dopamine receptor agonists was dopamine > quinpirole > 6,7-aminodihydroxytetralin > 5,6-aminodihydroxytetralin. Dopamine receptor antagonists also showed high affinity, with a rank order of haloperidol > chlorpromazine > domperidone > (+)-butaclamol > (-)-sulpiride = (+)-sulpiride > (+)-SCH23390 > (-)-butaclamol. [125I]L-750,667, bound to D4 receptors in a stereoselective manner with (+)-butaclamol showing higher activity than its respective enantiomer (-)-butaclamol. These results show that [125I]L-750,667 is a novel, highly selective radioligand for dopamine D4 receptors and may be used to investigate the dopamine D4 receptor population in the central nervous system.
Mol Pharmacol 1996 Dec
PMID:Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor. 896 90

Dopamine receptor isoforms were examined in the cochlea of the CBA(J) mouse by RT-PCR analysis and nucleotide sequencing, utilizing primers specific for known dopamine receptor isoforms. Cochlear cDNA sequences corresponding to dopamine D2(long) and D3 receptors were amplified, whereas those representing D1A, D1B, D2(short), and D4 were not detected. Utilizing quantitative competitive PCR analysis, relative levels of dopamine receptor transcripts were found to be 0.002, 0.014, 0.016, and 1.000 for D2(long) cochlea, D3 cochlea, D3 brain, and D2(long) brain, respectively. In the context of previously published findings, the current work provides key quantitative evidence necessary to establish that dopamine is a neurotransmitter in the auditory inner ear.
Brain Res Mol Brain Res 1997 Feb
PMID:Quantitative analysis of dopamine receptor messages in the mouse cochlea. 903 Jul 11

Dopamine acts, under appropriate conditions, as a selective neurotoxin. This toxicity is attributed to the autoxidation of the neurotransmitter into a reactive quinone that covalently modifies cellular macromolecules (i.e. proteins and nucleic acids). The oxidation of the catecholamine to a quinone is greatly accelerated by the enzyme tyrosinase. There is controversy, however, as to whether or not tyrosinase is expressed in human brain. In the present study, RT-PCR was utilized to demonstrate the presence of tyrosinase mRNA in post-mortem human brain tissues. Using gene-specific amplification primers, specific tyrosinase amplicons were detected following analysis of RNA from substantia nigra of four individuals. Analysis of cerebellar RNA from the same individuals produced no amplification products. Control reactions performed in the absence of reverse transcriptase failed to generate PCR products for any tissue tested. Three amplicons were subjected to direct DNA sequencing and all proved to be identical with tyrosinase sequences, thus obviating the possibility of amplification of a related gene. It is clear, therefore, that the tyrosinase gene is expressed in the human substantia nigra, lending support to previous studies describing tyrosinase-like activity and immunoreactive protein in the brain. This enzyme could be central to dopamine neurotoxicity as well as contribute to the neurodegeneration associated with Parkinson's disease.
Brain Res Mol Brain Res 1997 Apr
PMID:Tyrosinase mRNA is expressed in human substantia nigra. 910 85

Dopamine-glutamate interactions within discrete neural circuits are increasingly recognized as potential substrates for dysregulation in schizophrenia, and as a result, potential targets for pharmacological intervention in this illness. We examined the regulation, by haloperidol (2 mg kg-1 day-1) and clozapine (20 mg kg-1 day-1), of the mRNAs encoding the four AMPA receptor subunits (gluR1-gluR4), three low-affinity kainate receptor subunits (gluR5-gluR7), and two high-affinity kainate subunits (KA1 and KA2) in the rat hippocampal formation and associated entorhinal cortex. A complex and differential pattern of AMPA and kainate subunit mRNA regulation by clozapine and haloperidol was observed in this study. Both drugs caused significant alterations of most of these mRNAs, but in a heterogeneous and region-specific fashion. These data suggest that these antipsychotic drugs alter the expression of the genes encoding the subunits that express ionotropic glutamate receptors. Given the importance of glutamatergic mechanisms and the hippocampal formation in schizophrenia, these data suggest a potential substrate for neurotransmitter dysregulation in this illness, as well as a potential target for therapeutic intervention.
Mol Psychiatry 1996 Mar
PMID:Differential regulation of hippocampal AMPA and kainate receptor subunit expression by haloperidol and clozapine. 911 9

Dopamine is believed to play a major role in the manifestation of attention deficit hyperactivity disorder (ADHD), which affects 3-6% of school-age children and shows evidence of familiarity. The dopamine D4 receptor, which is preferentially distributed in cortical and limbic regions of the brain, is currently of major interest because of the high degree of functionally relevant variability in its gene (DRD4), and the association of this gene with Novelty Seeking behavior. We examined the variability in the length of a region of DRD4 that contains a 48-bp repeat sequence in children with ADHD and controls matched for ethnicity. ADHD children differed from controls in that the 7-fold repeat form of DRD4 occurred significantly more frequently than in the control sample. This form of the receptor has previously been shown to mediate a blunted intracellular response to dopamine. Although ADHD is likely to be multifactorial in its etiology and its heritability is likely to be polygenetic, the present findings suggest that polymorphic variation in the gene encoding the D4 dopamine receptor may be a contributing factor in the expression of symptoms associated with ADHD.
Mol Psychiatry 1996 May
PMID:Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. 911 26


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