Les canaux calciques dépendants du voltage au coeur de la douleur

Les canaux calciques dépendants du voltage représentent une des voies principales d’entrée du calcium dans la cellule nerveuse où ils participent activement à l’excitabilité cellulaire et aux processus moléculaires de la transmission synaptique. Ils ont, de ce fait, été depuis longtemps la cible pharmacologique d’analgésiques et ce, avant même que leur implication dans la physiologie de la nociception ait réellement été démontrée. Ces dernières années, la caractérisation moléculaire de plus en plus fine de ces canaux et de leurs sous-unités régulatrices, ainsi que la démonstration de leur implication dans les processus nociceptifs, a permis de définitivement considérer ces structures comme des cibles pharmacologiques de premier choix pour le traitement de la douleur. La recherche d’inhibiteurs spécifiques des canaux calciques dépendants du voltage laisse ainsi entrevoir le développement de nouvelles molécules analgésiques fortement prometteuses.Voltage-dependent calcium channels represent a major pathway of calcium entry into neurons, where they participate actively to cell excitability and to the molecular processes of synaptic transmission. For that reason, they have been the direct or indirect pharmacological targets of analgesics and this long before their implication in the physiology of nociception had been demonstrated. These last years, the still more refined molecular characterization of these channels and their associated regulatory subunits and the demonstration of their implication in nociceptive processes indicates that these structures are prime pharmacological targets for the management of pain. Herein, we detail the recent breakthroughs on calcium channel structure, function and pharmacology, review the implication of calcium channels in the transmission of nociception, and evaluate their importance as targets for the treatment of pain perception. The search for specific inhibitors of voltage-dependent calcium channels appears as a prelude to the development of new promising analgesic molecules

[Role of P/Q calcium channel in familial hemiplegic migraine]

International audienceVoltage-dependent calcium channels constitute one of the main pathways of calcium entry into neurons. They are the principal actors of synaptic transmission by controlling the release of neurotransmitters. They also contribute to numerous other cell functions, such as gene expression or synaptogenesis. These channels, by their essential cell functions, are at the origin of numerous channelopathies resulting from mutations of the genes encoding their different subunits. Familial Hemiplegic Migraine (FHM) represents one such example of these channelopathies. In this human disease, genetic studies have demonstrated the implication of the CACNA1A gene in a type 1 form of FHM. This gene encodes for the Ca(v)2.1 subunit of P/Q calcium channels and is the target of numerous mutations affecting the properties of channel activity. The question on how discrete mutations of this gene are able to alter the activity of the channel and contribute to the physiopathology of FHM remains an open question. The functional characterization of mutated channels in various heterologous expression systems, as well as in vivo in an animal model, provides a molecular scheme of the physiopathology of FHM in which neurons, astrocytes and blood circulation act in concert

How do G proteins directly control neuronal Ca2+ channel function?

Ca2+ entry into neuronal cells is modulated by the activation of numerous G-protein-coupled receptors (GPCRs). Much effort has been invested in studying direct G-protein-mediated inhibition of voltage-dependent CaV2 Ca2+ channels. This inhibition occurs through a series of convergent modifications in the biophysical properties of the channels. An integrated view of the structural organization of the Gbetagamma-dimer binding-site pocket within the channel is emerging. In this review, we discuss how variable geometry of the Gbetagamma binding pocket can yield distinct sets of channel inhibition. In addition, we propose specific mechanisms for the regulation of the channel by G proteins that take into account the regulatory input of each Gbetagamma binding element

Gulosibacter molinativorax gen. nov., sp. nov., a molinate-degrading bacterium, and classification of ‘Brevibacterium helvolum’ DSM 20419 as Pseudoclavibacter helvolus gen. nov., sp. nov.

A Gram-positive, molinate-degrading bacterium, strain ON4T (=DSM 13485T=LMG 21909T), was isolated from a mixed bacterial culture able to mineralize the herbicide molinate. The strain was strictly aerobic, oxidase- and catalase-positive and non-acid-fast, with a growth temperature of 10–41 6C. It contained the major menaquinone MK-9 and a cell-wall peptidoglycan based on D-ornithine. 16S rDNA sequence analysis revealed that the strain formed a distinct line of descent in the family Microbacteriaceae, showing the highest 16S rDNA similarity (~95 %) to members of the genus Curtobacterium and ‘Brevibacterium helvolum’ DSM 20419 (=ATCC 13715). The latter was reported to have the cell-wall peptidoglycan type B2c and the major menaquinone MK-9, which are typical of Clavibacter, but it is clearly separated from this genus at the phylogenetic level. Based on low values of 16S rDNA sequence similarity to previously described genera and their distinctive phenotypic characteristics, it is proposed that strains ON4T and ‘B. helvolum’ DSM 20419 be classified as two novel genera and species, with the respective names Gulosibacter molinativorax gen. nov., sp. nov. and Pseudoclavibater helvolus gen. nov., sp. nov

Importance of voltage-dependent inactivation in N-type calcium channel regulation by G-proteins.: Channel inactivation in G-protein regulation

International audienceDirect regulation of N-type calcium channels by G-proteins is essential to control neuronal excitability and neurotransmitter release. Binding of the G(betagamma) dimer directly onto the channel is characterized by a marked current inhibition ("ON" effect), whereas the pore opening- and time-dependent dissociation of this complex from the channel produce a characteristic set of biophysical modifications ("OFF" effects). Although G-protein dissociation is linked to channel opening, the contribution of channel inactivation to G-protein regulation has been poorly studied. Here, the role of channel inactivation was assessed by examining time-dependent G-protein de-inhibition of Ca(v)2.2 channels in the presence of various inactivation-altering beta subunit constructs. G-protein activation was produced via mu-opioid receptor activation using the DAMGO agonist. Whereas the "ON" effect of G-protein regulation is independent of the type of beta subunit, the "OFF" effects were critically affected by channel inactivation. Channel inactivation acts as a synergistic factor to channel activation for the speed of G-protein dissociation. However, fast inactivating channels also reduce the temporal window of opportunity for G-protein dissociation, resulting in a reduced extent of current recovery, whereas slow inactivating channels undergo a far more complete recovery from inhibition. Taken together, these results provide novel insights on the role of channel inactivation in N-type channel regulation by G-proteins and contribute to the understanding of the physiological consequence of channel inactivation in the modulation of synaptic activity by G-protein coupled receptors

Aureobacterium resistens sp. nov., exhibiting vancomycin resistance and teicoplanin susceptibility

Two similar strains of a coryneform bacterium were isolated from human clinical material. Both strains were resistant to vancomycin but susceptible to teicoplanin. Detailed biochemical, chemotaxonomical, and molecular genetic investigations revealed that both isolates were members of a hitherto undescribed species of the genus Aureobacterium. The name Aureobacterium resistens sp. nov. is proposed for the new bacterium and the type strain is CCUG 3831

Eine monumentale Dankesgabe: Trajans Neubau der Heiligen Straße von Milet nach Didyma

Durch Bau- bzw. Dedikationsinschriften in lateinischer und griechischer Sprache ist seit langem bekannt, dass Trajan die Heilige Straße von Milet zum Heiligtum des Apollon von Didyma neu anlegen ließ. Eine weitere, hier publizierte griechische Inschrift mit neuen Einzelheiten gibt Anlass, die gesamte vorhandene epigraphische Präsentation in revidierter Form vorzulegen und die Inszenierung des Bauprogramms mit seinem politischen Hintergrund eingehend zu analysieren. Es dokumentiert – so das Ergebnis – dauerhaft Trajans cura, liberalitas und vor allem pietas in Form einer monumentalen Dankesgabe an die Stadt und ihren Orakelgott, der die Herrschaft des Kaisers vorausgesagt hatte.Through building and dedicatory inscriptions written in Latin and Greek, it has long been known that Trajan had the sacred road from Miletus to the sanctuary of Apollo at Didyma reconstructed. Another Greek inscription, to be published in this article, provides new details and offers the occasion to present the entire epigraphical documentation in a revised form, analysing in-depth the political staging of this building programme. Hence, it records Trajan’s cura, liberalitas, and above all his pietas in a permanent way by offering a monumental gift to the city and her oracle god who had foretold the emperor’s rule.On sait depuis longtemps, grâce au témoignage de dédicaces épigraphiques en latin et en grec, que Trajan fit rénover la route sacrée qui mène de Milet jusqu’au sanctuaire d’Apollon de Didymes. Une des inscriptions grecques, publiée ici avec de nouveaux détails, donne l’occasion de reprendre, en le présentant sous une forme révisée, l’ensemble du dossier épigraphique disponible et d’analyser de manière détaillée la mise en scène du programme de construction dans son contexte politique. Cette documentation met en relief – comme le révèle le résultat – sur le long terme la cura de Trajan, sa liberalitas et avant tout sa pietas qui se manifestent sous la forme d’un don de reconnaissance monumental envers la ville et envers sa divinité oraculaire qui avait prédit le règne de l’empereur