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1.
Exp Cell Res ; 300(1): 35-42, 2004 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-15383312

RESUMEN

The phosphorylation of myosin light chain (MLC) is a key regulatory point in the control of cellular morphology. Evidence suggests that RhoA-a member of the Rho GTPase family-regulates MLC phosphorylation via Rho kinase (ROK). Neurones display subtle alterations in their cytoarchitecture during the synaptic plasticity following high-frequency stimulation. We have recently demonstrated that RhoB, and not RhoA, is activated in neurones by high-frequency stimulation. However, the downstream consequences of RhoB activation in cells are unclear. In this study, we tested the hypothesis that RhoB might stimulate neuronal MLC phosphorylation. Transfection of PC12 cells with constitutively active RhoB increased MLC phosphorylation. Conversely, dominant-negative RhoB vectors reduced MLC phosphorylation. The effect of RhoB was attenuated by pretreatment with a selective ROK inhibitor. This confirms that Rho GTPases are important regulators of MLC phosphorylation, but suggests that, in neuronal cells, the control is exerted via RhoB rather than RhoA.


Asunto(s)
Cadenas Ligeras de Miosina/metabolismo , Neuronas/metabolismo , Proteína de Unión al GTP rhoB/metabolismo , Potenciales de Acción/genética , Animales , Células COS , Forma de la Célula/genética , Citoesqueleto/genética , Citoesqueleto/metabolismo , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/genética , Técnicas In Vitro , Mutación/genética , Plasticidad Neuronal/genética , Neuronas/enzimología , Células PC12 , Fosforilación , Ratas , Transducción de Señal/genética , Transfección , Proteína de Unión al GTP rhoA/metabolismo , Proteína de Unión al GTP rhoB/antagonistas & inhibidores , Proteína de Unión al GTP rhoB/genética
2.
Neuropharmacology ; 46(6): 879-87, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15033347

RESUMEN

There is accumulating evidence that Ras, and Ras-related GTPases of the Rho family, such as RhoA, RhoB and Rac1, are involved in synaptic plasticity in brain regions such as the hippocampus. We have recently shown that Rho family GTPases are activated by synaptic transmission in the CA1 region of the hippocampus. Since the function of these GTPases is dependent on post-translational isoprenylation by either farnesyl or geranylgeranyl transferases, we tested the hypothesis that inhibition of isoprenylation would modify long-term potentiation (LTP). Farnesyl transferase inhibition, which suppressed activation of RhoB and Ras but not RhoA or Rac1, reduced the magnitude of LTP, while geranylgeranyl transferase inhibition, which inhibited RhoA and Rac1 but not RhoB, increased the magnitude of LTP. In addition, Y-27632, a specific inhibitor of a downstream effector of Rho GTPases-Rho-kinase-also increased the magnitude of LTP. This provides strong evidence that GTPases are important mediators of synaptic plasticity, and demonstrates that Rho-kinase acts to reduce the degree of plasticity at hippocampal synapses during LTP. Rho-kinase inhibitors have the unusual property of increasing the magnitude of LTP, and so may be potential cognitive enhancers.


Asunto(s)
GTP Fosfohidrolasas/metabolismo , Hipocampo/enzimología , Potenciación a Largo Plazo/fisiología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Inhibidores Enzimáticos/farmacología , GTP Fosfohidrolasas/antagonistas & inhibidores , Hipocampo/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Quinasas Asociadas a rho
3.
J Neurochem ; 87(5): 1309-12, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-14622110

RESUMEN

Ras-related GTPases of the Rho family, such as RhoA and RhoB, are well-characterised mediators of morphological change in peripheral tissues via their effects on the actin cytoskeleton. We tested the hypothesis that Rho family GTPases are involved in synaptic transmission in the CA1 region of the hippocampus. We show that GTPases are activated by synaptic transmission. RhoA and RhoB were activated by low frequency stimulation, while the induction of long-term potentiation (LTP) by high frequency stimulation was associated with specific activation of RhoB via NMDA receptor stimulation. This illustrates that these GTPases are potential mediators of synaptic transmission in the hippocampus, and raises the possibility that RhoB may play a role in plasticity at hippocampal synapses during LTP.


Asunto(s)
Hipocampo/fisiología , Transmisión Sináptica/fisiología , Proteínas de Unión al GTP rho/metabolismo , Animales , Células Cultivadas , Estimulación Eléctrica , Activación Enzimática/fisiología , Hipocampo/citología , Hipocampo/enzimología , Técnicas In Vitro , Potenciación a Largo Plazo/fisiología , Neuronas/metabolismo , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Proteína de Unión al GTP rhoB/metabolismo
4.
Brain Res Mol Brain Res ; 114(1): 1-8, 2003 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-12782387

RESUMEN

Small GTPases are monomeric guanine nucleotide binding proteins of 20-25 kDa mass. Rho GTPases belong to the Ras superfamily of small GTPases. The small GTPases of the Rho family have been shown to participate in the organisation of the actin cytoskeleton and signal transduction pathways leading to gene transcription. Recent evidence suggests that Rho family GTPases may play an important role in synaptic communication in the brain, and particularly in synatic plasticity. In this study the distribution of RhoA, RhoB, RhoG, Cdc42, and Rac1 was investigated in hippocampal and cerebellar tissue of adult rat brain using immunohistochemical techniques. Previous studies suggest that distribution of Rho family mRNA is uniform throughout these structures. Here we provide evidence for differences in expression of these proteins between different regions of the hippocampus, and between the molecular and granular layers in the cerebellum. These differences may prove important with regard to the physiological functions of Rho family GTPases.


Asunto(s)
Cerebelo/enzimología , Hipocampo/enzimología , Proteína de Unión al GTP rhoB/análisis , Factores de Edad , Animales , Western Blotting , GTP Fosfohidrolasas/análisis , Inmunohistoquímica , Células PC12 , Ratas , Proteína de Unión al GTP cdc42/análisis , Proteína de Unión al GTP rac1/análisis , Proteína de Unión al GTP rhoA/análisis
5.
Eur J Pharmacol ; 409(2): 159-66, 2000 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-11104829

RESUMEN

Superfusion of rat hippocampal slices with ATP induces a form of facilitation that has been poorly characterised. The present study has confirmed that at low concentrations of ATP (10 microM or less), an initial depression of evoked potential size is followed by a rebound facilitation which is not reproduced by alphabeta-methyleneATP, betagamma-methyleneATP, or the dinucleotide P1,P6-diadenosine hexaphosphate. The post-ATP facilitation could be prevented by the adenosine A1 receptor antagonists 8-phenyltheophylline or 1,3-dipropyl-8-cyclopentyltheophylline (50 nM), or superfusion of adenosine deaminase. The adenosine A2A receptor antagonist 8-(chlorostyryl)-caffeine did not affect the inhibition but prevented the post-ATP facilitation. The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid prevented the establishment of post-ATP facilitation. The post-ATP facilitation was also blocked by suramin at a concentration (50 microM) that does not block glutamate receptors. Suramin prevented the induction but not the maintenance phase of the post-ATP facilitation. The repeated induction of post-ATP facilitation by bursts of electrical stimulation designed to saturate the normal mechanisms of long-term potentiation prevented the induction of post-ATP facilitation. However, repeated applications of ATP to achieve saturation of its receptor did not prevent the subsequent induction of electrically evoked long-term potentiation. It is concluded that ATP can induce a form of synaptic facilitation which resembles only partially that induced by electrical stimulation and which may require the simultaneous activation of P1 and P2 receptors.


Asunto(s)
Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/farmacología , Cafeína/análogos & derivados , Hipocampo/efectos de los fármacos , Fosfato de Piridoxal/análogos & derivados , Transmisión Sináptica/efectos de los fármacos , Teofilina/análogos & derivados , Adenosina Desaminasa/farmacología , Animales , Cafeína/farmacología , Fosfatos de Dinucleósidos/farmacología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Hipocampo/fisiología , Técnicas In Vitro , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Antagonistas de Receptores Purinérgicos P1 , Fosfato de Piridoxal/farmacología , Ratas , Ratas Wistar , Suramina/farmacología , Teofilina/farmacología
6.
J Auton Nerv Syst ; 81(1-3): 244-8, 2000 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-10869728

RESUMEN

Although the emphasis in ATP research has been on postjunctional receptors, there is also evidence for presynaptic receptors regulating transmitter release in the autonomic nervous system. Recent work has attempted to identify similar mechanisms in the central nervous system. Some of the existing results can be explained by the metabolism of nucleotides to adenosine or adenosine 5'-monophosphate (AMP). However, studies of presynaptic effects using sensitive electrophysiological tests such as paired-pulse interactions indicate that nucleotides can act at presynaptic sites, but that their effects may be mediated by a release of adenosine. Results are also described which indicate that, under some conditions, nucleotides can mediate phenomena such as long-term potentiation, which probably involves a significant presynaptic element. In part these effects may involve a nucleotide-induced release of adenosine and the simultaneous activation of P1 and P2 receptors.


Asunto(s)
Receptores Presinapticos/fisiología , Receptores Purinérgicos P2/fisiología , Adenosina Trifosfato/fisiología , Animales , Sistema Nervioso Autónomo/fisiología , Sistema Nervioso Central/fisiología , Humanos , Potenciación a Largo Plazo/fisiología
7.
Eur J Pharmacol ; 362(1): 17-25, 1998 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-9865525

RESUMEN

Previous work has been carried out on the effects of adenosine on transmitter release and on the excitability of postsynaptic neurones, but little is known about the effects of adenosine on the coupling between the two. In this study, we examine the effects of specific adenosine receptor agonists and antagonists on the population excitatory postsynaptic potential (population EPSP) slope, the population spike amplitude, and the relationship between the two (E-S coupling) in the CA1 area of rat hippocampus. Activation of adenosine A1 receptors by adenosine or the selective agonist N6-cyclopentyladenosine resulted in a decrease of the population spike amplitude by a greater extent than could be accounted for by the decrease in population EPSP slope, resulting in a dissociation in the E-S relationship, reflected as a right-shift in the E-S curve. Activation of adenosine A2A receptors by the selective agonist 2-p-(2-carboxyethy)phenethylamino-5'-N-ethylcarboxamidoadeno sine (CGS 21680), or blockade by antagonists ZM 241385 and CP 66713 had no effect on evoked responses. However, when both adenosine A1 and A2A receptors were activated at the same time, a significant attenuation of the inhibitory effects of N6-cyclopentyladenosine on population spike amplitude was observed, resulting in a left-shift in the E-S curve. Intracellular recording indicated that N6-cyclopentyladenosine raised the threshold for spike induction by pulses of depolarising current, even at a concentration which did not produce hyperpolarisation of the neurone. At 30 nM, CGS 21680 prevented this effect of N6-cyclopentyladenosine, and this apparent antagonism was prevented by the A2A receptor antagonist ZM 241385. The results show that adenosine A1 receptors change the coupling between presynaptic transmitter release and postsynaptic cell firing, and that this effect is attenuated by A2A receptor activation.


Asunto(s)
Potenciales Postsinápticos Excitadores/efectos de los fármacos , Hipocampo/metabolismo , Receptores Purinérgicos P1/fisiología , Adenosina/análogos & derivados , Adenosina/farmacología , Animales , Masculino , Técnicas de Cultivo de Órganos , Fenetilaminas/farmacología , Agonistas del Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Pirazinas/farmacología , Ratas , Ratas Wistar , Triazinas/farmacología , Triazoles/farmacología
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