96 research outputs found

    Photo-antagonism of the GABAA receptor

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    Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor ÎČ and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation

    GABA Maintains the Proliferation of Progenitors in the Developing Chick Ciliary Marginal Zone and Non-Pigmented Ciliary Epithelium

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    GABA is more than the main inhibitory neurotransmitter found in the adult CNS. Several studies have shown that GABA regulates the proliferation of progenitor and stem cells. This work examined the effects of the GABAA receptor system on the proliferation of retinal progenitors and non-pigmented ciliary epithelial (NPE) cells. qRT-PCR and whole-cell patch-clamp electrophysiology were used to characterize the GABAA receptor system. To quantify the effects on proliferation by GABAA receptor agonists and antagonists, incorporation of thymidine analogues was used. The results showed that the NPE cells express functional extrasynaptic GABAA receptors with tonic properties and that low concentration of GABA is required for a baseline level of proliferation. Antagonists of the GABAA receptors decreased the proliferation of dissociated E12 NPE cells. Bicuculline also had effects on progenitor cell proliferation in intact E8 and E12 developing retina. The NPE cells had low levels of the Cl–transporter KCC2 compared to the mature retina, suggesting a depolarising role for the GABAA receptors. Treatment with KCl, which is known to depolarise membranes, prevented some of the decreased proliferation caused by inhibition of the GABAA receptors. This supported the depolarising role for the GABAA receptors. Inhibition of L-type voltage-gated Ca2+ channels (VGCCs) reduced the proliferation in the same way as inhibition of the GABAA receptors. Inhibition of the channels increased the expression of the cyclin-dependent kinase inhibitor p27KIP1, along with the reduced proliferation. These results are consistent with that when the membrane potential indirectly regulates cell proliferation with hyperpolarisation of the membrane potential resulting in decreased cell division. The increased expression of p27KIP1 after inhibition of either the GABAA receptors or the L-type VGCCs suggests a link between the GABAA receptors, membrane potential, and intracellular Ca2+ in regulating the cell cycle

    Spontaneously opening GABA receptors play a significant role in neuronal signal filtering and integration

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    Acknowledgements This work was supported by The Rosetrees Trust Research Grant A1066, RS MacDonald Seedcorn Award and Wellcome Trust—UoE ISSF Award to S.S. The authors thank Prof. David Wyllie (University of Edinburgh) and Prof. Dmitri Rusakov (UCL) for their valuable suggestions on paper preparation.Peer reviewedPublisher PD

    Échangeurs d’ions bidimensionnels

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    L’étude expĂ©rimentale des lois cinĂ©tiques de la rĂ©action d’échange des ions POCl62-/C1-, rĂ©action effectuĂ©e par trois Ă©changeurs d’ions bidimensionnels, et l’interprĂ©tation des rĂ©sultats obtenus montrent que ce processus est rĂ©gi par la diffusion des ions PoCl62- dans une couche macroscopique d’une Ă©paisseur Ă©gale Ă  environ 0,4 mm, du milieu liquide adjacent aux Ă©changeurs. Ceux-ci sont constituĂ©s par les couches monomolĂ©culaires des savons suivants : les chlorures d’hexadĂ©cyl- trimĂ©thylammonium, hexadĂ©cylpyridinium et hexadĂ©cyl- Ă©thyloldimĂ©thylammonium, adsorbĂ©s Ă  la surface du milieu aqueux qui contient les deux ions PoCl62- et Cl-

    Comment apporter des calories supplémentaires à une personne ùgée malade et dénutrie ?

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    ANGERS-BU MĂ©decine-Pharmacie (490072105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

    Apport de la clozapine dans le trouble bipolaire (Ă  propos d'un cas de trouble bipolaire Ă  cycles rapides)

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    La forme Ă  cycles rapides est une modalitĂ© Ă©volutive du trouble bipolaire particuliĂšrement difficile Ă  prendre en charge et frĂ©quemment responsable de rĂ©sistance aux traitements. La clozapine, chef de file des antipsychotiques atypiques, reprĂ©sente une alternative thĂ©rapeutique prometteuse bien que n'ayant pas d'autorisation officielle de mise sur le marchĂ© dans cette indication. De nombreuses Ă©tudes, malgrĂ© des faiblesses mĂ©thodologiques avĂ©rĂ©es, ont en effet suggĂ©rĂ© une efficacitĂ© curatrice et prophylactique de cet agent dans le trouble bipolaire, notamment dans les formes Ă  cycles rapides. Les effets secondaires hĂ©matologiques, potentiellement lĂ©taux, en limitent cependant l'usage, qui doit ĂȘtre essentiellement rĂ©servĂ© aux formes rĂ©sistantes dans un cadre lĂ©gal strict de prescription. La mise en place d'Ă©tudes aux stratĂ©gies plus rigoureuses pourrait permettre dans l'avenir de confirmer l'action thymorĂ©gulatrice de la clozapine et permettre un Ă©largissement de ses indications.NANTES-BU MĂ©decine pharmacie (441092101) / SudocSudocFranceF

    Échangeurs d’ions bidimensionnels

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    On mesure l’adsorption de plusieurs savons cationiques (sels d’ammonium quaternaire substituĂ©) et des ions PoCl62– Ă  la surface de leurs solutions aqueuses, au moyen de mĂ©thodes originales basĂ©es sur l’emploi de corps marquĂ©s aux radioĂ©lĂ©ments.Les cations organiques attirent les ions PoCl62– plus fortement que les ions Cl–. Il s’ensuit que les couches monomolĂ©culaires des savons cationiques adsorbĂ©s se comportent comme des Ă©changeurs d’ions bidimensionnels vis-Ă -vis des allions POCl62– et Cl–.A partir des rĂ©sultats des mesures d’adsorption nous calculons le coefficient d’échange sĂ©lectif ou de sĂ©lectivitĂ© qui pour nos systĂšmes est trĂšs Ă©levĂ©. Nous trouvons de plus que ce coefficient est fonction, d’une part, de la nature chimique (du caractĂšre hydrophobe en particulier) des cations organiques qui constituent les sites de l’échangeur d'ions bidimensionnel et, d’autre part, de la distance entre ces sites.Nous trouvons que l’enthalpie libre du processus d’échange sĂ©lectif entre les anions Ă©tudiĂ©s est une fonction linĂ©aire de la distance entre les sites.L’intĂ©rĂȘt des Ă©changeurs d’ions bidimensionnels en tant que modĂšle possible de la surface interne des rĂ©sines Ă©changeuses d’ions et des membranes biologiques est signalĂ©
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