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Accueil > Agenda > Les séminaires Jean Roche > Calcium and cannabinoids in modulation of inhibitory synaptic (...)

Calcium and cannabinoids in modulation of inhibitory (...)

Lundi 24 octobre 2005,11h, salle Lissitzky.


1 : J Physiol. 2005 Aug 25 ; [Epub ahead of print]

Dual Ca2+ modulation of glycinergic synaptic currents in rodent hypoglossal motoneurons.

Mukhtarov M, Ragozzino D, Bregestovski P.

Institut de Neurobiologie de la Mediterranee (INMED) INSERM U29, Marseille, France.

Glycinergic synapses are implicated in the coordination of reflex responses, sensory signal processing and pain sensation. Their activity is pre- and post-synaptically regulated, although mechanisms are poorly understood. Using patch-clamp recording and Ca2+ imaging in hypoglossal motoneurons from the rat and mouse brainstem slices, we address here the role of cytoplasmic Ca2+ (Cai) in glycinergic synapse modulation. Ca2+ influx through voltage-gated or NMDA receptor channels caused powerful transient inhibition of glycinergic IPSCs. This effect was accompanied by an increase in both the failure rate and paired-pulse ratio, as well as a decrease in the frequency of mIPSCs, suggesting a presynaptic mechanism of depression. Inhibition was reduced by the cannabinoid receptor antagonist SR141716A and occluded by the agonist WIN55,212-2, indicating involvement of endocannabinoid retrograde signaling. Conversely, in the presence of SR141716A, glycinergic IPSCs were potentiated postsynaptically by glutamate or NMDA, displaying a Ca2+-dependent increase in amplitude and decay prolongation. Both presynaptic inhibition and postsynaptic potentiation were completely prevented by strong Cai buffering (20 mM BAPTA). Our findings demonstrate two independent mechanisms by which Ca2+ modulates glycinergic synaptic transmission : (i) presynaptic inhibition of glycine release and (ii) postsynaptic potentiation of GlyR-mediated responses. This dual Ca2+-induced regulation might be important for feedback control of neurotransmission in a variety of glycinergic networks in mammalian nervous systems.

2 : Cell Calcium. 2005 May ;37(5):497-505.

Calcium and endocannabinoids in the modulation of inhibitory synaptic transmission.

Diana MA, Bregestovski P.

Laboratoire de Physiologie Cerebrale, CNRS UMR8118, 45, rue des Saints Peres 75006 Paris, France. marco.diana

Synapses in the central nervous system can be highly plastic devices, being able to modify their efficacy in relaying information in response to several factors. Calcium ions are often fundamental in triggering synaptic plasticity. Here, we will shortly review the effects induced by postsynaptic increases of calcium concentration at GABAergic and glycinergic synapses. Both postsynaptic and presynaptic mechanisms mediating changes in synaptic strength will be examined. Particular attention will be devoted to phenomena of retrograde signaling and, specifically, to the recently discovered role, played by the endocannabinoid system in retrograde synaptic modulation.

3 : Cell Calcium. 2005 May ;37(5):371-4.

Calcium in the function of the nervous system : new implications.

Bregestovski P, Spitzer N.

Institut de Neurobiologie de la Mediterranee (INMED), Parc Scientifique de Luminy, BP13, 13009 Marseille, France. pbreges

4 : J Physiol. 2001 Sep 15 ;535(Pt 3):741-55.

Activation of human alpha1 and alpha2 homomeric glycine receptors by taurine and GABA.

De Saint Jan D, David-Watine B, Korn H, Bregestovski P.

Laboratoire de Biologie Cellulaire et Moleculaire du Neurone, INSERM U261, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris cedex 15, France.

1. Two ligand binding alpha subunits, alpha1 and alpha2, of the human (H) glycine receptor (GlyR) are involved at inhibitory synapses in the adult and neonatal spinal cord, respectively. The ability of homomeric alphaH1 and alphaH2 GlyRs to be activated by glycine, taurine and GABA was studied in Xenopus oocytes or in the human embryonic kidney HEK-293 cell line. 2. In outside-out patches from HEK cells, glycine, taurine and GABA activated both GlyRs with the same main unitary conductance, i.e. 85 +/- 3 pS (n = 6) for alphaH1, and 95 +/- 5 pS (n = 4) for alphaH2. 3. The sensitivity of both alphaH1 and alphaH2 GlyRs to glycine was highly variable. In Xenopus oocytes the EC50 for glycine (EC50gly) was between 25 and 280 microM for alphaH1 (n = 44) and between 46 and 541 microM for alphaH2 (n = 52). For both receptors, the highest EC50gly values were found on cells with low maximal glycine responses. 4. The actions of taurine and GABA were dependent on the EC50gly : (i) their EC50 values were linearly correlated to EC50gly, with EC50tau approximately 10 EC50gly and EC50GABA approximately 500-800 EC50gly ; (ii) they could act either as full or weak agonists depending on the EC50gly. 5. The Hill coefficient (n(H)) of glycine remained stable regardless of the EC50gly whereas n(H) for taurine decreased with increasing EC50tau. 6. The degree of desensitization, evaluated by fast application of saturating concentrations of agonist on outside-out patches from Xenopus oocytes, was similar for glycine and taurine on both GlyRs and did not exceed 50 %. 7. Our data concerning the variations of EC50gly and the subsequent behaviour of taurine and GABA could be qualitatively described by the simple del Castillo-Katz scheme, assuming that the agonist gating constant varies whereas the binding constants are stable. However, the stability of the Hill coefficient for glycine was not explained by this model, suggesting that other mechanisms are involved in the modulation of EC50.

5 : Neuroscience. 2001 ;103(3):799-810.

Isolation and characterization of an alpha 2-type zebrafish glycine receptor subunit.

Imboden M, De Saint Jan D, Leulier F, Korn H, Goblet C, Bregestovski P.

Laboratoire de Biologie Cellulaire et Moleculaire du Neurone, INSERM U261, Institut Pasteur, 25, Rue du Dr Roux, F-75724, Paris Cedex 15, France.

The complementary DNA for a novel alpha subunit of the glycine receptor, alphaZ2, was isolated from a zebrafish adult brain library. The molecular characteristics, phylogenetic relationships and messenger RNA length of this alphaZ2 subunit show it to be an alpha2-type glycine receptor subunit isoform. The leader peptide however, diverges from those of known glycine receptor alpha isoforms. Recombinantly expressed in Xenopus oocytes, alphaZ2 formed functional glycine receptor channels. These homomeric channels were activated by glycine and taurine, with apparent affinities similar to those reported for zebrafish alphaZ1 glycine receptor, and were also effectively antagonized by nanomolar concentrations of strychnine. However, during prolonged applications of agonists, ionic currents of alphaZ2 receptor channels declined to a much lower steady-state level than those of alphaZ1, indicating different desensitization properties. Analysis of messenger RNA revealed that alphaZ2 is specifically expressed in adult brain tissue and present in both adult and embryonic zebrafish.This report contributes to the characterization of the diversity of glycine receptor isoforms in vertebrates.

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