共查询到20条相似文献,搜索用时 31 毫秒
1.
S. Z. Whetzel Y. H. Shih L. M. Georgic H. C. Akunne T. A. Pugsley 《Journal of neurochemistry》1997,69(6):2363-2368
Abstract: The dopamine (DA) D3 receptor antagonist PD 58491 {3-[4-[1-[4-[2-[4-(3-diethylaminopropoxy)phenyl]-benzoimidazol-1-yl-butyl]-1 H -benzoimidazol-2-yl]-phenoxy]propyl]diethylamine} bound with high affinity and selectivity to recombinant human DA D3 versus D2L and D4.2 receptors transfected into Chinese hamster ovary cells: K i values of 19.5 n M versus 2,362 and >3,000 n M , respectively. In contrast, the putative DA D3 receptor antagonist (+)-AJ76 displayed low affinity and selectivity for D3 versus D2L and D4.2 receptors (91 n M vs. 253 and 193 n M , respectively). In vitro, PD 58491 (1 n M −1µ M ) exhibited D3 receptor antagonist activity, reversing the quinpirole (10 n M )-induced stimulation of [3 H]thymidine uptake in D3 CHOpro-5 cells, but did not have any significant intrinsic activity by itself in this assay. PD 58491 did not decrease the γ-butyrolactone-induced increase in DA synthesis ( l -3,4-dihydroxyphenylalanine accumulation) in rat striatum, indicating that the compound possessed no in vivo DA D2 /D3 receptor agonist action at DA autoreceptors. PD 58491 (3–30 mg/kg, i.p.) generally did not alter DA or serotonin synthesis in either the striatum or mesolimbic region of rat brain. The D3 -preferring agonist PD 128907 decreased DA synthesis in striatum and mesolimbic regions, and this effect was attenuated by pretreatment with PD 58491. These findings support the hypothesis that DA D3 autoreceptors may in part modulate the synthesis and release of DA in striatum and mesolimbic regions. 相似文献
2.
Abstract: Cations of various size and charge were used as atomic scale probes of D1 and D2 dopamine receptors. Those cations that perturbed the binding of D1 - and D2 -selective dopamine receptor antagonists were identified by screening at 5 m M cation. Pseudo-noble-gas-configuration d-transition metals, such as zinc, exerted a complete inhibition of specific binding, whereas most other cations had little or no effect. The nature of zinc's actions was characterized by measuring the radioligand binding properties of [3 H]SCH-23390 and [3 H]methylspiperone to cloned D1A and D2L dopamine receptors in either the presence or absence of Zn2+ . Zinc exerts a low-affinity, dose-dependent, EDTA-reversible inhibition of the binding of subtype-specific antagonists primarily by decreasing the ligands' affinity for their receptors. The mechanism of zinc inhibition appears to be allosteric modulation of the dopamine receptor proteins because zinc increases the dissociation constant ( K D ) of ligand binding, Schild-type plots of zinc inhibition reach a plateau, and zinc accelerates antagonist dissociation rates. Here we demonstrate the effect of zinc on the binding of D1 - and D2 -selective antagonists to cloned dopamine receptors and show that the inhibition by zinc is through a dose-dependent, reversible, allosteric, two-state modulation of dopamine receptors. 相似文献
3.
Stephen J. Morris Diane M. Beatty Bibie M. Chronwall 《Journal of neurochemistry》1998,71(3):1329-1332
Abstract: GABAB and dopamine D2 receptors, both of which acutely inhibit adenylyl cyclase and high voltage-activated Ca2+ channels (HVA-CCs), are found in high levels in the melanotrope cells of the pituitary intermediate lobe. Chronic D2 receptor agonist application in vitro has been reported to result in inhibition of HVA-CC activity by down-regulation. Here we report that chronic GABAB , but not GABAA , agonist treatment also resulted in HVA-CC inhibition. Two GABAB receptor variants have been cloned and shown to inhibit adenylyl cyclase in HEK-293 cells. We have constructed an antisense deoxynucleotide knockdown-type probe that is complementary to 18 bp from the point at which the two sequences first become homologous. Chronic coincubation with baclofen and GABAB antisense nucleotide completely eliminated the inhibition of the channels by baclofen alone but had no reversing effect on HVA-CC inhibition by the D2 agonist quinpirole. A scrambled, missense nucleotide also had no reversing effect. Incubation with a D2 antisense knockdown probe eliminated the ability of a D2 agonist to inhibit the channels but had no effect on baclofen blockade. These results show the existence an R1a/R1b type of GABAB receptor, which, like the D2 receptor, is coupled to chronic HVA-CC inhibition in melanotropes. 相似文献
4.
5.
Abstract: We have assessed the ability of the serotonergic antagonist mianserin to modulate the number and functional activity of human 5-hydroxytryptamine2A (5-HT2A ) and 5-HT2C receptors stably expressed in the human neuroblastoma cell line SH-SY5Y. Incubation of cells expressing the 5-HT2A receptor with mianserin (100 n M ) for 24 h caused a significant decrease (48%) in the binding capacity of [3 H]ketanserin. This receptor down-regulation was associated with a corresponding decrease in the maximal production of inositol phosphates induced by 5-HT but not by carbachol. Exposure of cells expressing the 5-HT2C receptor to mianserin (100 n M ) for 72 h but not for 24 h similarly resulted in a significant reduction (44%) in [3 H]mesulergine binding. Corresponding analysis of inositol phosphate production by 5-HT at the 5-HT2C receptor after incubation with mianserin showed no change in maximal response after 24 h. No change in the binding capacity of either radioligand was seen after incubation with mianserin for 1 h. A decrease in the binding affinity of both radioligands was also observed after mianserin treatment, but this decrease was similar after 1 h of incubation to that seen after 24 or 72 h, and was probably due to the retention of mianserin within the tissue. We conclude that antagonist down-regulation is evident at human 5-HT2A and 5-HT2C receptors stably expressed in a human neuroblastoma cell line and is probably mediated by a direct action of mianserin at the receptor. 相似文献
6.
Naoko Ozaki Kayoko Moroi †Tomoko Kadota Shiro Suzuki ‡Ken Kadota 《Journal of neurochemistry》1994,62(2):582-591
Abstract: Coated vesicles (CVs) isolated from bovine striatal tissue were examined to determine whether they are associated with dopamine signal systems consisting of dopamine D1 and D2 receptors, G proteins, and adenylate cyclase. Dopamine receptors in CVs were characterized by a dopamine D1 receptor antagonist, [3 H]SCH 23390, and a dopamine D2 receptor antagonist, [3 H]-spiroperidol. The bindings of both ligands were specifically saturable and reversible with a dissociation constant ( K D ) of 0.65 and 0.5 n M , respectively. Dopaminergic antagonists and agonists inhibited the specific bindings of [3 H]SCH 23390 and [3 H]spiroperidol in a stereoselective and concentration-dependent manner with an appropriate rank order potency for dopamine D1 or D2 receptors. The regulations of the agonist binding by guanyl-5-ylimidodiphosphate were observed. ADP ribosylation of the CVs with [32 P]NAD demonstrated predominant labeling of bands of Mr 47,000–52,000, 42,000–45,000, and 40,000-39,000, which corresponded to the known molecular weights of the α subunits of Gs and Gi proteins. The presence of α and β subunits of G proteins in the CVs was also confirmed by immunoblotting assay. Adenylate cyclase activity, which was stimulated by SKF 38393 and inhibited by dopamine D2 receptor agonists, was present in the CVs. These findings suggest that the dopamine D1 and D2 receptors in the CVs couple with adenylate cyclase via Gs /Gi protein. 相似文献
7.
Nuria Cabello Jorge Gandía† Daniela C. G. Bertarelli Masahiko Watanabe‡ Carme Lluís Rafael Franco Sergi Ferré§ Rafael Luján¶ Francisco Ciruela† 《Journal of neurochemistry》2009,109(5):1497-1507
G protein-coupled receptors are known to form homo- and heteromers at the plasma membrane, but the stoichiometry of these receptor oligomers are relatively unknown. Here, by using bimolecular fluorescence complementation, we visualized for the first time the occurrence of heterodimers of metabotropic glutamate mGlu5 receptors (mGlu5 R) and dopamine D2 receptors (D2 R) in living cells. Furthermore, the combination of bimolecular fluorescence complementation and bioluminescence resonance energy transfer techniques, as well as the sequential resonance energy transfer technique, allowed us to detect the occurrence receptor oligomers containing more than two protomers, mGlu5 R, D2 R and adenosine A2A receptor (A2A R). Interestingly, by using high-resolution immunoelectron microscopy we could confirm that the three receptors co-distribute within the extrasynaptic plasma membrane of the same dendritic spines of asymmetrical, putative glutamatergic, striatal synapses. Also, co-immunoprecipitation experiments in native tissue demonstrated the existence of an association of mGlu5 R, D2 R and A2A R in rat striatum homogenates. Overall, these results provide new insights into the molecular composition of G protein-coupled receptor oligomers in general and the mGlu5 R/D2 R/A2A R oligomer in particular, a receptor oligomer that might constitute an important target for the treatment of some neuropsychiatric disorders. 相似文献
8.
Xiao-Hui Wang Wei Jian Zhu Lorenzo Corsi Snezana Ikonomovic William R. Paljug Stefano Vicini Dennis R. Grayson 《Journal of neurochemistry》1998,71(2):693-704
Abstract: We investigated the effect of chronically blocking NMDA receptor stimulation to examine changes in GABAA receptor expression and pharmacology in cerebellar granule cells at different stages of maturation. We have previously shown that NMDA-selective glutamate receptor stimulation alters GABAA receptor pharmacology in cerebellar granule neurons in vitro by altering the levels of selective subunits. When NMDA receptor stimulation is blocked with MK-801 during the first week in vitro, a decrease in the α1, γ2S, and γ2L receptor subunit mRNAs occurred. When present only during the second week, changes were limited to the α1 and γ2L mRNAs. Finally, if MK-801 was present during the first week and removed during the second week, these changes reversed. Whole-cell voltage-clamp recordings showed that treatment with MK-801 during either the first or second week increased the EC50 of the receptors for GABA and attenuated the potentiation mediated by flunitrazepam. Last, these properties were reversed if MK-801 was removed after the first week in vitro. Our results suggest that MK-801 reversibly inhibits GABAA receptor maturation by modulating receptor subunit expression and that the altered pharmacological responses appear to be dominated by changes in the levels of allosteric modulation mediated by the γ2 receptor subunit. 相似文献
9.
Cristina Missale Flora Boroni Sandra Sigala Laura Castelletti Pierre Falardeau Roberto Dal Toso† Marc G. Caron PierFranco Spano 《Journal of neurochemistry》1994,62(3):907-915
Abstract: In anterior pituitary cells or when transfected into host cell lines, the D2 dopamine receptor inhibits adenylyl cyclase and activates potassium channels. The GH-3 pituitary tumor cell line, which lacks functional D2 receptors, responds to epidermal growth factor (EGF) by expressing a D2 receptor that, paradoxically, couples to potassium channel activation but poorly inhibits adenylyl cyclase; this was correlated with a pronounced increase in α subunit of the G protein G13 . In this study we have investigated the effects of EGF on the transduction mechanisms of D2 receptors in GH4C1 cells transfected and permanently overexpressing the rat short D2 receptor. Activation of D2 receptors in these cells resulted in both inhibition of adenylyl cyclase and opening of potassium channels and inhibition of prolactin release by both cyclic AMP-dependent and independent mechanisms. Exposure of the transfected GH4C1 cells to EGF caused a dramatic decrease in the coupling efficiency of the D2 receptor to inhibit cyclic AMP-dependent responses, leaving its activity toward potassium channels unchanged. The EGF treatment led to the concomitant increase in the membrane content of G13 protein. These results suggest that the transmembrane signaling specificity of G protein-coupled receptors can be modulated by the relative amounts of different G proteins at the cell membrane. 相似文献
10.
Sutton LP Honardoust D Mouyal J Rajakumar N Rushlow WJ 《Journal of neurochemistry》2007,102(1):153-169
Protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3) and members of the Wnt signal transduction pathway were recently found to be altered in schizophrenia and targeted by antipsychotic drugs. In the current study, selected Wnt signalling proteins were investigated to determine if they are altered by the antipsychotics clozapine or haloperidol in the rat prefrontal cortex. Pheochromocytoma (PC12) and neuroblastoma (SH-SY5Y) cells were also used to elucidate how antipsychotics generated the pattern of changes observed in vivo . Western blotting (WB) revealed that treatment with haloperidol or clozapine caused an up-regulation of Wnt-5a, dishevelled-3, Axin, total and phosphorylated GSK-3 and β-catenin protein levels. Treatment of PC12 and SH-SY5Y cells with a variety of pharmacological agents as well as the over-expression of several Wnt related proteins failed to mimic the pattern observed in vivo following antipsychotic treatment. However, the over-expression of dishevelled-3 nearly perfectly duplicated the changes observed in vivo . Immunoprecipitations (IP) conducted using protein isolated from the rat prefrontal cortex indicated that dishevelled-3 is associated with the D2 dopamine receptor thereby suggesting that antipsychotics may act on dishevelled-3 via D2 dopamine receptors to initiate a cascade of downstream changes involving Axin, GSK-3 and β-catenin that may help to alleviate psychosis in schizophrenic patients. 相似文献
11.
Activation of Microtubule-Associated Protein Kinase (Erk) and p70 S6 Kinase by D2 Dopamine Receptors 总被引:4,自引:4,他引:0
Gavin I. Welsh David A. Hall rew Warnes Philip G. Strange Christopher G. Proud 《Journal of neurochemistry》1998,70(5):2139-2146
Abstract: The ability of human and rat D2(short) and D2(long) dopamine receptors to activate microtubule-associated protein (MAP) kinase (Erk1/2) and p70 S6 kinase has been investigated in recombinant cells expressing these receptors. In cells expressing the D2(short) receptor, dopamine activated both enzymes in a transient manner but with very different time courses, with activation of Erk being much quicker. Activation of both enzymes by dopamine was dose-dependent and could be prevented by a range of selective dopamine antagonists. Excellent correlations were observed between the potencies of the antagonists for blocking enzyme activation and their affinities for the D2 dopamine receptor. Activation of Erk and of p70 S6 kinase via the D2 dopamine receptors was prevented by pretreatment of the cells with pertussis toxin, indicating the involvement of G proteins of the Gi or Go family. Inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase) were found to block substantially, but not completely, activation of p70 S6 kinase by dopamine, suggesting the involvement of PI 3-kinase-dependent and -independent signalling pathways in its control by dopamine. p70 S6 kinase activation was completely blocked by rapamycin. In the case of Erk, activation was partially blocked by wortmannin or LY294002, indicating a possible link with PI 3-kinase. 相似文献
12.
Abstract: Quantitative autoradiography of [3 H]MK-801 binding was used to characterize regional differences in N -methyl- d -aspartate (NMDA) receptor pharmacology in rat CNS. Regionally distinct populations of NMDA receptors were distinguished on the basis of regulation of [3 H]MK-801 binding by the NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). CPP inhibited [3 H]MK-801 binding in outer cortex (OC) and medial cortex (MC) with apparent K i values of 0.32-0.48 μ M , whereas in the medial striatum (MS), lateral striatum (LS), CA1, and dentate gyrus (DG) of hippocampus, apparent K i values were 1.1-1.6 μ M . In medial thalamus (MT) and lateral thalamus (LT) the apparent K i values were 0.78 μ M . In the presence of added glutamate (3 μ M ), the relative differences in apparent K i values between regions maintained a similar relationship with the exception of the OC. Inhibition of [3 H]MK-801 binding by the glycine site antagonist 7-chlorokynurenic acid (7-ClKyn) distinguished at least two populations of NMDA receptors that differed from populations defined by CPP displacement. 7-ClKyn inhibited [3 H]MK-801 binding in OC, MC, MS, and LS with apparent K i values of 6.3-8.6 μ M , whereas in CA1, DG, LT, and MT, K i values were 11.4-13.6 μ M . In the presence of added glycine (1 μ M ), the relative differences in apparent K i values were maintained. Under conditions of differential receptor activation, regional differences in NMDA receptor pharmacology can be detected using [3 H]MK-801 binding. 相似文献
13.
Abstract: The 7315c pituitary tumor cell expresses a homogeneous population of dopamine receptors that are functionally similar to brain dopamine D2 receptors. [3 H]-Sulpiride binding to 7315c cell homogenates was specific and saturable, and K i values for compounds to compete for these sites were highly correlated with values for the same compounds at D2 receptors in brain. Dopamine maximally inhibited ∼65% of forskolin-stimulated cyclase activity in cell membranes. Some D2 agonists had lower efficacies, suggesting that some compounds are partial agonists at this receptor. Removal of GTP from the assay buffer or pretreatment of the tissue with pertussis toxin abolished the inhibition of adenylyl cyclase by dopamine. Immunodetection of most of the known Gα subunits revealed that Gi1 , Gi2 , Gi3 , Go , Gq , and Gs are present in the 7315c membrane. Pretreatment with the AS antibody (which recognizes the C-terminal regions of Gαi1 and Gαi2 ) significantly attenuated the inhibition of adenylyl cyclase activity by dopamine, whereas antibodies to C-terminal regions of the other Gα subunits had no effect. These findings suggest that the dopamine D2 receptor regulates cyclase inhibition predominantly via Gi1 and/or Gi2 and that the 7315c tumor cells provide a useful model for studying naturally expressed dopamine D2 receptors in the absence of other dopamine receptor subtypes. 相似文献
14.
Abstract: Despite a high degree of sequence homology, the dopamine D2 and D3 receptors have substantially different second messenger coupling properties. We have used chimeric D2 /D3 receptors to investigate the contribution of the intracellular loops to the signaling properties of these receptors. In HEK 293 cells, D2 receptors inhibit prostaglandin E1 -stimulated cyclic AMP levels by >90%, whereas D3 receptors inhibit cyclic AMP accumulation by only 20%. In chimeras that have the second or third intracellular loop, or both loops simultaneously, switched between the D2 and D3 receptors, the maximal inhibition of adenylyl cyclase is 60–90%. In addition, the potency of quinpirole to inhibit adenylyl cyclase activity at some of the chimeras is altered compared with the wild-type receptors. It appears that the intracellular loops of the D3 receptor are capable of interacting with G proteins, as when these loops are expressed in the D2 receptor, the chimeras inhibit adenylyl cyclase similarly to the wild-type D2 receptor. Our data suggest that the overall conformation of the D3 receptor may be such that it interacts with G proteins only weakly, but when the intracellular loops are expressed in another context or the D3 receptor structure is altered by the introduction of D2 receptor sequence, this constraint may be lifted. 相似文献
15.
Activation of adenosine A1 and A2A receptors modulates dopamine D2 receptor-induced responses in stably transfected human neuroblastoma cells 总被引:1,自引:0,他引:1
Salim H Ferré S Dalal A Peterfreund RA Fuxe K Vincent JD Lledo PM 《Journal of neurochemistry》2000,74(1):432-439
Adenosine can influence dopaminergic neurotransmission in the basal ganglia via postsynaptic interaction between adenosine A2A and dopamine D2 receptors. We have used a human neuroblastoma cell line (SH-SY5Y) that was found to express constitutively moderate levels of adenosine A1 and A2A receptors (approximately 100 fmol/mg of protein) to investigate the interactions of A2A/D2 receptors, at a cellular level. After transfection with human D2L receptor cDNA, SH-SY5Y cells expressed between 500 and 1,100 fmol of D2 receptors/mg of protein. In membrane preparations, stimulation of adenosine A2A receptors decreased the affinity of dopamine D2 receptors for dopamine. In intact cells, the calcium concentration elevation induced by KCI treatment was moderate, and dopamine had no effect on either resting intracellular free Ca2+ concentration ([Ca2+]i) or KCI-induced responses. In contrast, pretreatment with adenosine deaminase for 2 days dramatically increased the elevation of [Ca2+]i evoked by KCI, which then was totally reversed by dopamine. The effects induced by 48-h adenosine inactivation were mimicked by application of adenosine A1 antagonists and could not be further reversed by acute activation of either A1 or A2A receptors. Acute application of the selective A2 receptor agonist CGS-21680 counteracted the D2 receptor-induced [Ca2+]i responses. The present study shows that SH-SY5Y cells are endowed with functional adenosine A2A and A1 receptors and that A2A receptors exert an antagonistic acute effect on dopamine D2 receptor-mediated functions. In contrast, A1 receptors induce a tonic modulatory role on these dopamine functions. 相似文献
16.
Irreversible blockade of sigma-1 receptors by haloperidol and its metabolites in guinea pig brain and SH-SY5Y human neuroblastoma cells 总被引:3,自引:0,他引:3
We evaluated the effect of haloperidol (HP) and its metabolites on [3 H](+)-pentazocine binding to σ1 receptors in SH-SY5Y human neuroblastoma cells and guinea pig brain P1 , P2 and P3 subcellular fractions. Three days after a single i.p. injection in guinea pigs of HP (but not of other σ1 antagonists or (−)-sulpiride), [3 H](+)-pentazocine binding to brain membranes was markedly decreased. Recovery of σ1 receptor density to steady state after HP-induced inactivation required more than 30 days. HP-metabolite II (reduced HP, 4-(4-chlorophenyl)-α-(4-fluorophenyl)-4-hydroxy-1-piperidinebutanol), but not HP-metabolite I (4-(4-chlorophenyl)-4-hydroxypiperidine), irreversibly blocked σ1 receptors in guinea pig brain homogenate and P2 fraction in vitro . We found similar results in SH-SY5Y cells, which suggests that this process may also take place in humans. HP irreversibly inactivated σ1 receptors when it was incubated with brain homogenate and SH-SY5Y cells, but not when incubated with P2 fraction membranes, which suggests that HP is metabolized to inactivate σ1 receptors. Menadione, an inhibitor of the ketone reductase activity that leads to the production of HP-metabolite II, completely prevented HP-induced inactivation of σ1 receptors in brain homogenates. These results suggest that HP may irreversibly inactivate σ1 receptors in guinea pig and human cells, probably after metabolism to reduced HP. 相似文献
17.
Gary E. Duncan†‡ George R. Breese† Hugh E. Criswell Kevin B. Johnson Uta B. Schambra Robert A. Mueller Marc G. Caron§ Robert T. Fremeau Jr. ¶# 《Journal of neurochemistry》1993,61(4):1255-1262
Abstract: The role of dopaminergic innervation on the postnatal developmental expression of D1 dopamine receptors was investigated. Bilateral destruction of dopa-mine-containing neurons was achieved by treating rats intracisternally with 6-hydroxydopamine (6-OHDA) on postnatal day 3, and rats were killed on day 21. To ensure effective reduction of D1 receptor activation by residual dopamine, a group of 6-OHDA-lesioned rats was given twice daily injections of the D1 receptor antagonist SCH-23390, from day 4 to 20. D1 dopamine receptor binding was assessed in the caudate—putamen, nucleus accumbens, and olfactory tubercle by quantitative autoradiographic analysis of [3 H]SCH-23390 binding. In addition, the relative amount of D1A receptor mRNA was assessed by in situ hybridization of a 35 S-labeled riboprobe. In the developing rats, neither the amount of [3 H]SCH-23390 binding nor the amount of D1A receptor mRNA was altered by 6-OHDA lesioning followed by chronic treatment with SCH-23390. Thus, bilateral destruction of dopamine-containing neurons and treatment with SCH-23390 in neonatal rats did not interfere with the developmental expression of D1 receptors or alter the levels of mRNA that code for this receptor protein. Treatment of intact rats with SCH-23390 from postnatal day 4 to 20 also did not alter [3 H]SCH-23390 binding or levels of D1 receptor mRNA. However, adult rats treated chronically with SCH-23390 exhibited increased [3 H]SCH-23390 binding but did not show a significant change in D1 receptor mRNA levels. 相似文献
18.
Abstract: The density of dopamine D2 -like receptors was determined using [3 H]emonapride binding in putamen tissue taken postmortem from schizophrenic subjects and matched controls. A 72% increase in number of these receptors was identified in the schizophrenics, although three patients not receiving antipsychotic drug treatment before death exhibited receptor densities in the control range. Displacement of 1 n M [3 H]emonapride binding by raclopride was used to define the contribution of the D4 subtype of dopamine receptors to total [3 H]emonapride binding. No evidence was obtained for the presence of D4 receptors in putamen tissue from either control or schizophrenic subjects, indicating that the increase in D2 -like receptor density in schizophrenia is due not to an increase in number of D4 sites in the disease, but to an up-regulation of D2 or D3 receptors probably induced by chronic treatment with antipsychotic drugs. 相似文献
19.
The N-Methyl-D-Aspartate Antagonist MK-801 Fails to Protect Dopaminergic Neurons from 1-Methyl-4- Phenylpyridinium Toxicity In Vitro 总被引:1,自引:0,他引:1
Francoise Finiels-Marlier Ann M. Marini Pat Williams Steven M. Paul 《Journal of neurochemistry》1993,60(5):1968-1971
Abstract: Recent reports suggest that NMDA receptor antagonists when administered in vivo can protect dopaminergic neurons from the toxic actions of MPP+ . In the present study the possible neuroprotective effects against MPP+ toxicity of the noncompetitive NMDA receptor antagonist MK-801 was studied in primary cultures of fetal rat mesencephalic dopamine neurons. MK-801 failed to protect dopaminergic neurons from MPP+ toxicity at concentrations that completely block NMDA-induced toxicity of these same neurons. In contrast to work carried out in cerebellar granule cells, MPP+ toxicity of mesencephalic dopamine neurons was unaffected by preexposure to subtoxic concentrations of either NMDA or cycloheximide. Our findings suggest that the toxic effects of MPP+ on dopaminergic neurons are not mediated through a direct interaction with the NMDA subtype of glutamate receptor. 相似文献
20.
C. J. Chang H. Ishii H. Yamamoto T. Yamamoto M. Spatz 《Journal of neurochemistry》1993,60(4):1483-1490
Abstract: To expand on the nature of regional cerebral vulnerability to ischemia, the release of dopamine (DA) and dopaminergic (D1 and D2 ) receptors were investigated in Mongolian gerbils subjected to bilateral carotid artery occlusion (15 min) alone or with reflow (1–2 h). Extracellular cortical and striatal content of DA and its metabolites was measured by microdialysis using HPLC with electrochemical detection. The kinetic properties of D1 and/or D2 receptor binding sites were determined in cortical and striatal membranes with the use of radiolabeled ligands (125 I-SCH23982 and [3 H]YM-09151-2, respectively). The ischemic release of DA from the striatum was greater (400-fold over preischemic level) than that from the cortex (12-fold over preischemic content). The affinity for the D1 -receptor ligand was lower ( K D = 1.248 ± 0.047 n M ) after ischemia than that for sham controls ( K D = 0.928 ± 0.032 n M, p < 0.001). The number of binding sites for D2 receptors decreased in striatum ( B max = 428 ± 18.4 fmol/mg of protein) after ischemia compared with sham controls ( B max = 510 ± 25.2 fmol/mg of protein, p < 0.05). D1 or D2 binding sites were not changed either in the ischemic cortex or postischemic striatum and cortex. The findings strongly suggest that the ischemic release of DA from striatum is associated with early transient changes in D1 - and D2 -mediated DA neurotransmission. 相似文献