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1.
Nature ; 553(7689): 455-460, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29342142

RESUMO

Locomotion is a fundamental motor function common to the animal kingdom. It is implemented episodically and adapted to behavioural needs, including exploration, which requires slow locomotion, and escape behaviour, which necessitates faster speeds. The control of these functions originates in brainstem structures, although the neuronal substrate(s) that support them have not yet been elucidated. Here we show in mice that speed and gait selection are controlled by glutamatergic excitatory neurons (GlutNs) segregated in two distinct midbrain nuclei: the cuneiform nucleus (CnF) and the pedunculopontine nucleus (PPN). GlutNs in both of these regions contribute to the control of slower, alternating-gait locomotion, whereas only GlutNs in the CnF are able to elicit high-speed, synchronous-gait locomotion. Additionally, both the activation dynamics and the input and output connectivity matrices of GlutNs in the PPN and the CnF support explorative and escape locomotion, respectively. Our results identify two regions in the midbrain that act in conjunction to select context-dependent locomotor behaviours.


Assuntos
Marcha/fisiologia , Mesencéfalo/citologia , Mesencéfalo/fisiologia , Vias Neurais/fisiologia , Animais , Comportamento Exploratório , Ácido Glutâmico/metabolismo , Camundongos , Neurônios/metabolismo , Fatores de Tempo
2.
Transl Psychiatry ; 7(4): e1088, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28398338

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by motor impairment and a wide range of non-motor symptoms, including sleep disorders and cognitive and affective deficits. In this study, we used a mouse model of PD based on 6-hydroxydopamine (6-OHDA) to examine the effect of thioperamide, a histamine H3 receptor antagonist, on circadian activity, recognition memory and anxiety. A partial, bilateral 6-OHDA lesion of the striatum reduces motor activity during the active phase of the 24 h cycle. In addition, the lesion disrupts the endogenous circadian rhythm observed when mice are maintained in constant darkness. Administration of thioperamide to 6-OHDA-lesion mice rescues the normal rest/activity cycle. Moreover, thioperamide counteracts the deficit of novel object recognition produced by 6-OHDA. Our experiments show that this memory impairment is accompanied by disrupted gamma oscillations in the hippocampus, which are also rescued by thioperamide. In contrast, we do not observe any modification of the anxiogenic effect of 6-OHDA in response to administration of thioperamide. Our results indicate that thioperamide may act as a multifunctional drug, able to counteract disruptions of circadian rhythm and cognitive deficits associated with PD.


Assuntos
Ansiedade/tratamento farmacológico , Nível de Alerta/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Rememoração Mental/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Piperidinas/uso terapêutico , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Ansiedade/fisiopatologia , Nível de Alerta/fisiologia , Ritmo Circadiano/fisiologia , Ritmo Gama/efeitos dos fármacos , Ritmo Gama/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Masculino , Rememoração Mental/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Parkinsonianos/fisiopatologia
3.
Neuropharmacology ; 66: 53-64, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22664304

RESUMO

Restoring the balance between excitatory and inhibitory circuits in the basal ganglia, following the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta, represents a major challenge to treat patients affected by Parkinson's disease (PD). The imbalanced situation in favor of excitation in the disease state may also accelerate excitotoxic processes, thereby representing a potential target for neuroprotective therapies. Reducing the excitatory action of glutamate, the major excitatory neurotransmitter in the basal ganglia, should lead to symptomatic improvement for PD patients and may promote the survival of DA neurons. Recent studies have focused on the modulatory action of metabotropic glutamate (mGlu) receptors on neurodegenerative diseases including PD. Group III mGlu receptors, including subtypes 4, 7 and 8, are largely expressed in the basal ganglia. Recent studies highlight the use of selective mGlu4 receptor positive allosteric modulators (PAMs) for the treatment of PD. Here we review the effects of newly-designed group-III orthosteric agonists on neuroprotection, neurorestoration and reduction of l-DOPA induced dyskinesia in animal models of PD. The combination of orthosteric mGlu4 receptor selective agonists with PAMs may open new avenues for the symptomatic treatment of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.


Assuntos
Agonistas de Aminoácidos Excitatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Receptores de Glutamato Metabotrópico/agonistas , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/tratamento farmacológico , Agonistas de Aminoácidos Excitatórios/farmacologia , Modelos Neurológicos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo
4.
Neuroscience ; 156(3): 515-26, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18765270

RESUMO

Transgenic mice with overexpression of the caspase-inhibitor, X-chromosome-linked inhibitor of apoptosis protein (XIAP) in Purkinje cell (PC) and in retinal bipolar cells (RBCs) were produced to study the regulation of cell death. Unexpectedly, an increased neurodegeneration was observed in the PCs in these L7-XIAP mice after the third postnatal week with the mice exhibiting severe ataxia. The loss of PCs was independent of Bax as shown by crossing the L7-XIAP mice with Bax gene-deleted mice. Electron microscopy revealed intact organelles in PCs but with the stacking of ER cisterns indicative of cell stress. Immunostaining for cell death proteins showed an increased phosphorylation of c-Jun in the PCs, suggesting an involvement in cell degeneration. Apart from PCs, the number of RBCs was decreased in adult retina in line with the expression pattern for the L7 promoter. The data show that overexpression of the anti-apoptotic protein XIAP in vulnerable neurons leads to enhanced cell death. The mechanisms underlying this neurodegeneration can be related to the effects of XIAP on cell stress and altered cell signaling.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Degeneração Neural/etiologia , Células de Purkinje/metabolismo , Células Bipolares da Retina/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Ataxia/genética , Comportamento Animal , Cerebelo/citologia , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica de Varredura/métodos , Degeneração Neural/genética , Degeneração Neural/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-jun/metabolismo , Células de Purkinje/ultraestrutura , Células Bipolares da Retina/ultraestrutura , Transfecção/métodos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteína X Associada a bcl-2/deficiência
5.
Prog Neurobiol ; 83(5): 277-92, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17646043

RESUMO

Adenosine A2A receptors are highly enriched in the basal ganglia system. They are predominantly expressed in enkephalin-expressing GABAergic striatopallidal neurons and therefore are highly relevant to the function of the indirect efferent pathway of the basal ganglia system. In these GABAergic enkephalinergic neurons, the A2A receptor tightly interacts structurally and functionally with the dopamine D2 receptor. Both by forming receptor heteromers and by targeting common intracellular signaling cascades, A2A and D2 receptors exhibit reciprocal antagonistic interactions that are central to the function of the indirect pathway and hence to basal ganglia control of movement, motor learning, motivation and reward. Consequently, this A2A/D2 receptors antagonistic interaction is also central to basal ganglia dysfunction in Parkinson's disease. However, recent evidence demonstrates that, in addition to this post-synaptic site of action, striatal A2A receptors are also expressed and have physiological relevance on pre-synaptic glutamatergic terminals of the cortico-limbic-striatal and thalamo-striatal pathways, where they form heteromeric receptor complexes with adenosine A1 receptors. Therefore, A2A receptors play an important fine-tuning role, boosting the efficiency of glutamatergic information flow in the indirect pathway by exerting control, either pre- and/or post-synaptically, over other key modulators of glutamatergic synapses, including D2 receptors, group I metabotropic mGlu5 glutamate receptors and cannabinoid CB1 receptors, and by triggering the cAMP-protein kinase A signaling cascade.


Assuntos
Adenosina/metabolismo , Gânglios da Base/metabolismo , Vias Neurais/metabolismo , Neurônios/metabolismo , Receptor A2A de Adenosina/metabolismo , Transmissão Sináptica/fisiologia , Animais , Gânglios da Base/anatomia & histologia , Encefalinas/metabolismo , Humanos , Vias Neurais/anatomia & histologia , Receptores de Neurotransmissores/metabolismo , Ácido gama-Aminobutírico/metabolismo
6.
Exp Neurol ; 194(1): 66-75, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15899244

RESUMO

Dyskinesia (abnormal involuntary movements) is a common complication of l-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. Dopamine (DA) denervated mice can exhibit behavioral and cellular signs of dyskinesia when they are treated with l-DOPA, but the clinical relevance of this animal model remains to be established. In this study, we have examined the pharmacological profile of l-DOPA-induced abnormal involuntary movements (AIMs) in the mouse. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) in the striatum. The animals were treated chronically with daily doses of l-DOPA that were sufficient to ameliorate akinetic features without inducing overt signs of dyskinesia upon their first administration. In parallel, other groups of mice were treated with antiparkinsonian agents that do not induce dyskinesia when administered de novo, that is, the D2/D3 agonist ropinirole, and the adenosine A2a antagonist KW-6002. During 3 weeks of treatment, l-DOPA-treated mice developed AIMs affecting the head, trunk and forelimb on the side contralateral to the lesion. These movements were not expressed by animals treated with ropinirole or KW-6002 at doses that improved forelimb akinesia. The severity of l-DOPA-induced rodent AIMs was significantly reduced by the acute administration of compounds that have been shown to alleviate l-DOPA-induced dyskinesia both in parkinsonian patients and in rat and monkey models of Parkinson's disease (amantadine, -47%; buspirone, -46%; riluzole, -33%). The present data indicate that the mouse AIMs are indeed a functional equivalent of l-DOPA-induced dyskinesia.


Assuntos
Gânglios da Base/efeitos dos fármacos , Gânglios da Base/fisiopatologia , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/fisiopatologia , Levodopa/efeitos adversos , Agonistas do Receptor A2 de Adenosina , Adrenérgicos/efeitos adversos , Amantadina/farmacologia , Animais , Antiparkinsonianos/farmacologia , Gânglios da Base/metabolismo , Buspirona/farmacologia , Progressão da Doença , Agonistas de Dopamina/farmacologia , Esquema de Medicação , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/metabolismo , Indóis/farmacologia , Levodopa/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Purinas/farmacologia , Receptor A2A de Adenosina/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Reprodutibilidade dos Testes , Riluzol/farmacologia , Resultado do Tratamento
7.
Cell Mol Life Sci ; 61(7-8): 857-72, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15095008

RESUMO

The popularity of caffeine as a psychoactive drug is due to its stimulant properties, which depend on its ability to reduce adenosine transmission in the brain. Adenosine A(1) and A(2A) receptors are expressed in the basal ganglia, a group of structures involved in various aspects of motor control. Caffeine acts as an antagonist to both types of receptors. Increasing evidence indicates that the psychomotor stimulant effect of caffeine is generated by affecting a particular group of projection neurons located in the striatum, the main receiving area of the basal ganglia. These cells express high levels of adenosine A(2A) receptors, which are involved in various intracellular processes, including the expression of immediate early genes and regulation of the dopamine- and cyclic AMP-regulated 32-kDa phosphoprotein DARPP-32. The present review focuses on the effects of caffeine on striatal signal transduction and on their involvement in caffeine-mediated motor stimulation.


Assuntos
Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Cafeína/metabolismo , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/metabolismo , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso , Animais , Gânglios da Base/citologia , Gânglios da Base/metabolismo , Dopamina/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina , Inibidores Enzimáticos/metabolismo , Humanos , Neurônios/metabolismo , Fármacos Neuroprotetores/metabolismo , Doença de Parkinson/metabolismo , Fosfoproteínas/metabolismo , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptores de Dopamina D2/metabolismo , Transdução de Sinais , Transmissão Sináptica/fisiologia
8.
Eur J Neurosci ; 13(4): 773-80, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11207812

RESUMO

In the striatum, dopamine release is inhibited by activation of dopamine D(2) autoreceptors. Changes in dopamine release have been attributed to changes in the synthesis of dopamine, which is regulated via phosphorylation of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines. Here, we have studied the involvement of dopamine D(2) receptors in the regulation of TH phosphorylation at distinct seryl residues, using phosphorylation site-specific antibodies and a preparation of rat striatal slices. The D(2) receptor agonist, quinpirole, reduced basal TH phosphorylation at Ser40 but not at Ser19 or Ser31. Quinpirole was also able to reduce the increase in Ser40 phosphorylation caused by forskolin, an activator of adenylyl cyclase, without affecting the increase in Ser19 phosphorylation produced by the glutamate receptor agonist, N-methyl-D-aspartate (NMDA). In addition, the dopamine D(2) receptor agonist reduced both basal and forskolin-stimulated activity of TH, measured as 3,4-dihydroxyphenylalanine (DOPA) accumulation. Quinpirole decreased phosphorylation of Ser40 induced by okadaic acid, an inhibitor of protein phosphatase 1 and 2A and Ro-20-1724, a phosphodiesterase inhibitor. In contrast, quinpirole did not affect the increase in Ser40 phosphorylation caused by the cAMP analogue, 8-Br-cAMP. These data indicate that, in the striatum, activation of dopamine D(2) receptors results in selective inhibition of TH phosphorylation at Ser40 via reduction of the activity of adenylyl cyclase. They also provide a molecular mechanism accounting for the ability of dopamine D(2) autoreceptors to inhibit dopamine synthesis and release from nigrostriatal nerve terminals.


Assuntos
Corpo Estriado/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Fosfosserina/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Receptores de Dopamina D2/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Animais , Colforsina/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/enzimologia , Di-Hidroxifenilalanina/biossíntese , Dopamina/biossíntese , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Masculino , N-Metilaspartato/farmacologia , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Ácido Okadáico/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 1 , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/efeitos dos fármacos
9.
J Neurochem ; 75(1): 248-57, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10854268

RESUMO

The role of the dopamine- and cyclic AMP-regulated phosphoprotein of M(r) 32,000 (DARPP-32) in dopaminergic regulation of gene transcription in striatum and globus pallidus was examined. Mice with targeted disruption of the gene encoding DARPP-32, its homologue, inhibitor-1, or both, were used. Pharmacological characterization showed that mutant mice had normal basal levels of dopamine D(1) and D(2) receptors and adenosine A(2A) receptors. Basal expression levels of the striatonigral-specific neuropeptides substance P and prodynorphin and the immediate early genes c-fos and NGFI-A were also unaltered in mutant mice. A full D(1) receptor agonist, SKF 82958, up-regulated the expression of these neuropeptides and immediate early genes significantly more in wild-type mice than in mice lacking DARPP-32. Moreover, the additive stimulation of SKF 82958 and quinelorane, a D(2) receptor agonist, on c-fos mRNA in globus pallidus was significantly decreased in DARPP-32 and DARPP-32/I-1 knockout mice. No changes in dopamine receptor-induced gene expression were found in I-1 knockout mice. These results demonstrate an important involvement of DARPP-32 in dopamine receptor-mediated regulation of gene expression both in striatal neurons, which are enriched in DARPP-32, and in pallidal neurons, which do not contain DARPP-32.


Assuntos
Regulação da Expressão Gênica , Proteínas do Tecido Nervoso , Fosfoproteínas/fisiologia , Receptores de Dopamina D1/fisiologia , Transcrição Gênica , Animais , Benzazepinas/farmacologia , Núcleo Caudado/metabolismo , Corpo Estriado/metabolismo , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos , Globo Pálido/metabolismo , Camundongos , Camundongos Knockout , Núcleo Accumbens/metabolismo , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Quinolinas/farmacologia , RNA Mensageiro/metabolismo , Receptor A2A de Adenosina , Receptores de Dopamina D2/metabolismo , Receptores Purinérgicos P1/metabolismo
10.
J Neurochem ; 74(6): 2470-7, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10820208

RESUMO

The activity of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of dopamine, is stimulated by phosphorylation. In this study, we examined the effects of activation of NMDA receptors on the state of phosphorylation and activity of tyrosine hydroxylase in rat striatal slices. NMDA produced a time-and concentration-dependent increase in the levels of phospho-Ser(19)-tyrosine hydroxylase in nigrostriatal nerve terminals. This increase was not associated with any changes in the basal activity of tyrosine hydroxylase, measured as DOPA accumulation. Forskolin, an activator of adenylyl cyclase, stimulated tyrosine hydroxylase phosphorylation at Ser(40) and caused a significant increase in DOPA accumulation. NMDA reduced forskolin-mediated increases in both Ser(40) phosphorylation and DOPA accumulation. In addition, NMDA reduced the increase in phospho-Ser(40)-tyrosine hydroxylase produced by okadaic acid, an inhibitor of protein phosphatase 1 and 2A, but not by a cyclic AMP analogue, 8-bromo-cyclic AMP. These results indicate that, in the striatum, glutamate decreases tyrosine hydroxylase phosphorylation at Ser(40) via activation of NMDA receptors by reducing cyclic AMP production. They also provide a mechanism for the demonstrated ability of NMDA to decrease tyrosine hydroxylase activity and dopamine synthesis.


Assuntos
Núcleo Caudado/citologia , Receptores de N-Metil-D-Aspartato/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Animais , Especificidade de Anticorpos , Domínio Catalítico/imunologia , Núcleo Caudado/química , Núcleo Caudado/enzimologia , Colforsina/farmacologia , Di-Hidroxifenilalanina/biossíntese , Inibidores Enzimáticos/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Técnicas In Vitro , Masculino , N-Metilaspartato/farmacologia , Neurônios/química , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Ácido Okadáico/farmacologia , Oxidopamina , Fosforilação , Ratos , Ratos Sprague-Dawley , Serina/metabolismo , Simpatolíticos , Tirosina 3-Mono-Oxigenase/química , Tirosina 3-Mono-Oxigenase/imunologia
11.
Proc Natl Acad Sci U S A ; 97(4): 1856-60, 2000 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-10677546

RESUMO

Dopamine D(1), dopamine D(2), and adenosine A(2A) receptors are highly expressed in striatal medium-sized spiny neurons. We have examined, in vivo, the influence of these receptors on the state of phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). DARPP-32 is a potent endogenous inhibitor of protein phosphatase-1, which plays an obligatory role in dopaminergic transmission. A dose-dependent increase in the state of phosphorylation of DARPP-32 occurred in mouse striatum after systemic administration of the D(2) receptor antagonist eticlopride (0.1-2.0 mg/kg). This effect was abolished in mice in which the gene coding for the adenosine A(2A) receptor was disrupted by homologous recombination. A reduction was also observed in mice that had been pretreated with the selective A(2A) receptor antagonist SCH 58261 (10 mg/kg). The eticlopride-induced increase in DARPP-32 phosphorylation was also decreased by pretreatment with the D(1) receptor antagonist SCH 23390 (0.125 and 0.25 mg/kg) and completely reversed by combined pretreatment with SCH 23390 (0.25 mg/kg) plus SCH 58261 (10 mg/kg). SCH 23390, but not SCH 58261, abolished the increase in DARPP-32 caused by cocaine (15 mg/kg). The results indicate that, in vivo, the state of phosphorylation of DARPP-32 and, by implication, the activity of protein phosphatase-1 are regulated by tonic activation of D(1), D(2), and A(2A) receptors. The results also underscore the fact that the adenosine system plays a role in the generation of responses to dopamine D(2) antagonists in vivo.


Assuntos
AMP Cíclico/farmacologia , Dopamina/farmacologia , Fosfoproteínas/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores Purinérgicos P1/metabolismo , Animais , Benzazepinas/farmacologia , Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Fosfoproteína 32 Regulada por cAMP e Dopamina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Proteína Fosfatase 1 , Pirimidinas/farmacologia , Receptor A2A de Adenosina , Receptores de Dopamina D1/metabolismo , Salicilamidas/farmacologia , Triazóis/farmacologia
12.
Prog Neurobiol ; 59(4): 355-96, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10501634

RESUMO

It is well known that the nucleoside adenosine exerts a modulatory influence in the central nervous system by activating G protein coupled receptors. Adenosine A2A receptors, the subject of the present review, are predominantly expressed in striatum, the major area of the basal ganglia. Activation of A2A receptors interferes with effects mediated by most of the principal neurotransmitters in striatum. In particular, the inhibitory interactions between adenosine acting on A2A receptors and dopamine acting on D2 receptors have been well examined and there is much evidence that A2A receptors may be a possible target for future development of drugs for treatment of Parkinson's disease, schizophrenia and affective disorders. Our understanding of the role of striatal A2A receptors has increased dramatically over the last few years. New selective antibodies, antagonist radioligands and optimized in situ hybridization protocols have provided detailed information on the distribution of A2A receptors in rodent as well as primate striatum. Studies on the involvement of A2A receptors in the regulation of DARPP-32 and the expression of immediate early genes, such as nerve growth factor-induced clone A and c-fos, have pointed out an important role for these receptors in regulating striatopallidal neurotransmission. Moreover, by using novel selective antagonists for A2A receptors and transgenic mice lacking functional A2A receptors, crucial information on the behavioral role of striatal A2A receptors has been provided, especially concerning their involvement in the stimulatory action of caffeine and the anti-Parkinsonian properties of A2A receptor antagonists. In the present review, current knowledge on the distribution, biochemistry and function of striatal A2A receptors is summarized.


Assuntos
Neostriado/química , Receptores Purinérgicos P1/química , Animais , Neostriado/fisiologia , Receptor A2A de Adenosina , Receptores Purinérgicos P1/fisiologia
13.
J Neurochem ; 73(4): 1492-501, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10501194

RESUMO

Our previous studies showed that dopamine inhibits Na+,K+-ATPase activity in acutely dissociated neurons from striatum. In the present study, we have found that in this preparation, dopamine inhibited significantly (by approximately 25%) the activity of the alpha3 and/or alpha2 isoforms, but not the alpha1 isoform, of Na+,K+-ATPase. Dopamine, via D1 receptors, activates cyclic AMP-dependent protein kinase (PKA) in striatal neurons. Dopamine is also known to activate the calcium- and phospholipid-dependent protein kinase (PKC) in a number of different cell types. The PKC activator phorbol 12,13-dibutyrate reduced the activity of Na+,K+-ATPase alpha3 and/or alpha2 isoforms (by approximately 30%) as well as the alpha1 isoform (by approximately 15%). However, dopamine-mediated inhibition of Na+,K+-ATPase activity was unaffected by calphostin C, a PKC inhibitor. Dopamine did not affect the phosphorylation of Na+,K+-ATPase isoforms at the PKA-dependent phosphorylation site. Phorbol ester treatment did not alter the phosphorylation of alpha2 or alpha3 isoforms of Na+,K+-ATPase in neostriatal neurons but did increase the phosphorylation of the alpha1 isoform. Thus, in rat neostriatal neurons, treatment with either dopamine or PKC activators results in inhibition of the activity of specific (alpha3 and/or alpha2) isoforms of Na+,K+-ATPase, but this is not apparently mediated through direct phosphorylation of the enzyme. In addition, PKC is unlikely to mediate inhibition of rat Na+,K+-ATPase activity by dopamine in neostriatal neurons.


Assuntos
Dopamina/farmacologia , Neostriado/enzimologia , Neurônios/enzimologia , Proteína Quinase C/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Células COS , Células Cultivadas , Embrião de Mamíferos , Ativação Enzimática , Feminino , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Fosforilação , Gravidez , Ratos , Ratos Sprague-Dawley , ATPase Trocadora de Sódio-Potássio/genética , Transfecção
14.
Eur J Neurosci ; 11(7): 2589-92, 1999 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10383649

RESUMO

It is well documented that dopamine and dopamine D1 agonists convert the protein phosphatase-1 inhibitor, DARPP-32, from its dephosphorylated, inactive form into its Thr34-phosphorylated, active form, and that these effects on DARPP-32 constitute essential components of the mechanism by which dopamine and D1 agonists achieve their biological effects. In contrast to dopamine and D1 agonists, dopamine D2 agonists dephosphorylate and inactivate DARPP-32. Here we have examined the possibility that the biological effects of dopamine D2 receptor agonists might also involve DARPP-32. For this purpose, we have examined regulation of the activity of the electrogenic ion pump Na+,K+-ATPase, an established target for dopamine signalling. We have found that dopamine D1 agonists and dopamine D2 agonists inhibit Na+,K+-ATPase activity in dissociated cells from the mouse neostriatum and that, in each case, the effect is abolished in cells from mice deficient in DARPP-32. We conclude that DARPP-32 may play an obligatory role in dopaminergic signalling mediated both by D1 receptors and by D2 receptors.


Assuntos
Proteínas do Tecido Nervoso/fisiologia , Fosfoproteínas , Receptores de Dopamina D2/metabolismo , Animais , Agonistas de Dopamina/farmacologia , Fosfoproteína 32 Regulada por cAMP e Dopamina , Fenoldopam/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação/fisiologia , Neostriado/citologia , Neostriado/efeitos dos fármacos , Neostriado/enzimologia , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Quimpirol/farmacologia , Receptores de Dopamina D2/agonistas , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/metabolismo
15.
Neuroscience ; 88(4): 1005-8, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10336115

RESUMO

The vast majority of striatal neurons are GABAergic medium-sized spiny neurons. These cells receive glutamatergic input from the cortex, thalamus and limbic areas and dopaminergic input from the mesencephalon. Most relevant evidence indicates that dopamine D1 receptors are located on striatonigral projection neurons, and that adenosine A2A receptors and most dopamine D2 receptors are located on striatopallidal projection neurons (see, however, Refs I and 13). Here we have utilized regulation of the phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein of mol. wt 32,000 (DARPP-32) to study the possible interactions among nigrostriatal dopaminergic neurons and the two classes of dopaminoceptive target neurons. We show that, in striatal slices, the D2 receptor agonist, quinpirole, strongly inhibits the phosphorylation of DARPP-32 induced by either the D1 receptor agonist, SKF 81297, or the A2A receptor agonist, CGS 21680. Tetrodotoxin abolished the effect of quinpirole on the D1 agonist-induced but not the A2A agonist-induced phosphorylation of DARPP-32. These data indicate that: (i) adenosine A2A and dopamine D2 receptors interact within the same striatopallidal neurons, and (ii) D2 receptors present on the striatopallidal neurons modulate the effects of D1 receptors on the striatonigral neurons. Thus, a single neurotransmitter is capable of activating distinct classes of receptors on distinct populations of target neurons, which, in turn, interact with each other through intercellular communication.


Assuntos
Corpo Estriado/fisiologia , Globo Pálido/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Fosfoproteínas , Receptores de Dopamina D2/metabolismo , Substância Negra/fisiologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Benzazepinas/farmacologia , Corpo Estriado/citologia , Agonistas de Dopamina/farmacologia , Fosfoproteína 32 Regulada por cAMP e Dopamina , Globo Pálido/citologia , Fenetilaminas/farmacologia , Fosforilação/efeitos dos fármacos , Quimpirol/farmacologia , Ratos , Substância Negra/citologia , Tetrodotoxina/farmacologia
16.
Eur J Neurosci ; 11(6): 2182-6, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10336688

RESUMO

In the striatum, DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) is highly expressed by virtually all projection medium-sized spiny neurons. cAMP-dependent phosphorylation of DARPP-32 is stimulated via activation of dopamine D1 receptors in striatonigral neurons, and via activation of adenosine A2A receptors in striatopallidal neurons. In this study, we have examined the contribution of mu-, delta- and kappa-opioid receptors to the regulation of DARPP-32 phosphorylation, in rat striatal slices. The results show that, at low concentrations (100 pm-1 nm), the mu-opioid agonist, Tyr-D-Ala-Gly-N-Me-Phe-glycinol (DAMGO), inhibits the increase in DARPP-32 phosphorylation induced by activation of D1, but not by activation of A2A receptors. Conversely, the delta-receptor agonist, Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE), inhibits DARPP-32 phosphorylation induced by activation of A2A, but not by activation of D1 receptors. The kappa-receptor agonist, U50488, does not affect DARPP-32 phosphorylation induced by either D1 or A2A agonists. Thus, mu-opioid receptors interact with dopamine D1 receptors on striatonigral neurons, whereas delta-opioid receptors interact with adenosine A2A receptors on striatopallidal neurons. These results suggest that regulation of DARPP-32 phosphorylation is involved in mediating some of the effects exerted by enkephalin on striatal medium-sized spiny neurons.


Assuntos
Corpo Estriado/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Fosfoproteínas , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Animais , Corpo Estriado/citologia , Fosfoproteína 32 Regulada por cAMP e Dopamina , Ala(2)-MePhe(4)-Gly(5)-Encefalina , D-Penicilina (2,5)-Encefalina , Encefalinas/farmacologia , Técnicas In Vitro , Masculino , N-Metilaspartato/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
17.
Am J Physiol ; 275(6): F863-9, 1998 12.
Artigo em Inglês | MEDLINE | ID: mdl-9843902

RESUMO

Several indirect lines of evidence suggest that protein kinases and phosphatases modulate the activity of renal Na+-K+-ATPase. The aim of this study was to examine whether such regulation may occur via modulation of the state of phosphorylation of Na+-K+-ATPase. Slices from rat renal cortex were prelabeled with [32P]orthophosphate and incubated with the inhibitors of protein phosphatase (PP)-1 and PP-2A, okadaic acid (OA) and calyculin A (CL-A), respectively, the protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDBu), or the PP-2B inhibitor, FK-506. Phosphorylation of Na+-K+-ATPase alpha-subunit was evaluated by measuring the amount of [32P]phosphate incorporation into the immunoprecipitated protein. Incubation with either OA, CL-A, or PDBu caused four- to fivefold increases in the amount of [32P]phosphate incorporation into immunoprecipitated Na+-K+-ATPase alpha-subunit. OA and PDBu had a synergistic effect on the state of phosphorylation of Na+-K+-ATPase alpha-subunit. FK-506 did not affect Na+-K+-ATPase phosphorylation, neither alone nor in the presence of PDBu. Each of the drugs, OA, CL-A, and PDBu, inhibited the activity of Na+-K+-ATPase in microdissected proximal tubules. PDBu potentiated OA-induced inhibition of Na+-K+-ATPase activity. Inhibition of Na+-K+-ATPase required a lower dose of CL-A than of OA. On the basis of the inhibitory constant values of CL-A and OA for PP-1 and PP-2A, it is concluded that the tubular effect is mainly due to inhibition of PP-1. The PP-1 activity in rat renal cortex was approximately 1.5 nmol Pi. mg protein-1. min-1. Using a monoclonal anti-alpha antibody that fails to recognize the subunit when Ser23 is phosphorylated by PKC, we demonstrated that the dose response of PDBu inhibition of Na+-K+-ATPase correlated with the dose response of phosphorylation of the enzyme. The results suggest that the state of phosphorylation and activity of proximal tubular Na+-K+-ATPase are determined by the balance between the activities of protein kinases and phosphatases.


Assuntos
Inibidores Enzimáticos/farmacologia , Rim/enzimologia , Ácido Okadáico/farmacologia , Oxazóis/farmacologia , Dibutirato de 12,13-Forbol/farmacologia , Fosfoproteínas , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Fosfoproteína 32 Regulada por cAMP e Dopamina , Relação Dose-Resposta a Droga , Ativação Enzimática , Técnicas In Vitro , Masculino , Toxinas Marinhas , Proteínas do Tecido Nervoso/farmacologia , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Proteína Quinase C/metabolismo , Ratos , Ratos Sprague-Dawley
19.
Mol Med ; 4(4): 258-65, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9606178

RESUMO

BACKGROUND: The ion pump Na+,K(+)-ATPase is responsible for the secretion of cerebrospinal fluid from the choroid plexus. In this tissue, the activity of Na+,K(+)-ATPase is inhibited by serotonin via stimulation of protein kinase C-catalyzed phosphorylation. The choroid plexus is highly enriched in two phosphoproteins which act as regulators of protein phosphatase-1 activity, DARPP-32 and inhibitor-1. Phosphorylation catalyzed by cAMP-dependent protein kinase on a single threonyl residue converts DARPP-32 and inhibitor-1 into potent inhibitors of protein phosphatase-1. Previous work has shown that in the choroid plexus, phosphorylation of DARPP-32 and I-1 is enhanced by isoproterenol and other agents that activate cAMP-PK. We have now examined the possible involvement of the cAMP-PK/protein phosphatase-1 pathway in the regulation of Na+,K(+)-ATPase. MATERIALS AND METHODS: The state of phosphorylation of Na+,K(+)-ATPase was measured by determining the amount of radioactivity incorporated into the ion pump following immunoprecipitation from 32P-prelabeled choroid plexuses incubated with various drugs (see below). Two-dimensional phosphopeptide mapping was employed to identify the protein kinase involved in the phosphorylation of Na+,K(+)-ATPase. RESULTS: The serotonin-mediated increase in Na+,K(+)-ATPase phosphorylation is potentiated by okadaic acid, an inhibitor of protein phosphatases-1 and -2A, as well as by forskolin or the beta-adrenergic agonist, isoproterenol, activators of cAMP-dependent protein kinase. Two-dimensional phosphopeptide maps suggest that this potentiating action occurs at the level of a protein kinase C phosphorylation site. Forskolin and isoproterenol also stimulate the phosphorylation of DARPP-32 and protein phosphatase inhibitor-1, which in their phosphorylated form are potent inhibitors of protein phosphatase-1. CONCLUSIONS: The results presented here support a model in which okadaic acid, forskolin, and isoproterenol achieve their synergistic effects with serotonin through phosphorylation of DARPP-32 and inhibitor-1, inhibition of protein phosphatase-1, and a reduction of dephosphorylation of Na+,K(+)-ATPase at a protein kinase C phosphorylation site.


Assuntos
Proteínas de Transporte , Plexo Corióideo/enzimologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas , Proteína Quinase C/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Colforsina/farmacologia , Fosfoproteína 32 Regulada por cAMP e Dopamina , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Isoproterenol/farmacologia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Ácido Okadáico/farmacologia , Mapeamento de Peptídeos , Fosfopeptídeos/análise , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosforilação , Proteína Fosfatase 1 , Proteínas de Ligação a RNA/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/farmacologia , Transdução de Sinais/fisiologia
20.
Neuroscience ; 84(1): 223-8, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9522376

RESUMO

In the striatum, adenosine A2A and dopamine D1 receptors are segregated in striatopallidal and striatonigral projection neurons, respectively. In this study, we have examined the effects of activating adenosine A2A and dopamine D1 receptors on the state of phosphorylation of DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein of mol. wt 32,000), a potent endogenous regulator of protein phosphatase-1 that is highly expressed in striatal medium-sized spiny neurons. In rat striatal slices, the D1 receptor agonist SKF 81297 and the A2A receptor agonist CGS 21680 transiently increased the levels of phosphorylated DARPP-32 in a concentration-dependent manner. In the same preparation, the two agonists were also able to induce a significant increase in cyclic AMP formation. When striatal slices were incubated with a combination of CGS 21680 and SKF 81297, the effects of the two agonists on both DARPP-32 phosphorylation and cyclic AMP formation were additive. The maximal effects of SKF 81297 and CGS 21680 on DARPP-32 phosphorylation were of similar magnitude, and were completely abolished by the cyclic AMP-dependent protein kinase inhibitor, Rp-cAMPS. The present results show that DARPP-32 phosphorylation in the striatum is stimulated by adenosine, acting on A2A receptors, and dopamine, acting on D1 receptors, and that cyclic AMP is the mediator in both cases. Our data also suggest that dopamine and adenosine regulate the state of phosphorylation of DARPP-32 in distinct sub-populations of medium-sized spiny neurons expressing dopamine D1 and adenosine A2A receptors, respectively.


Assuntos
Corpo Estriado/fisiologia , AMP Cíclico/fisiologia , Inibidores Enzimáticos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosfoproteínas , Receptores de Dopamina D1/fisiologia , Receptores Purinérgicos P1/fisiologia , Transmissão Sináptica/fisiologia , Animais , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina , Masculino , Neurônios/fisiologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
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