RESUMEN
High densities of voltage-gated sodium (Nav) channels at nodes of Ranvier enable the rapid regeneration and propagation of the action potentials along myelinated axons. In demyelinating pathologies, myelin alterations lead to conduction slowing and even to conduction block. In order to unravel the mechanisms of conduction failure in inflammatory demyelinating diseases, we have examined two models of Guillain-Barré syndrome: the experimental allergic neuritis induced in the Lewis rat by immunization against peripheral myelin (EAN-PM) and against a neuritogenic P2 peptide (EAN-P2). We found that Nav channel clusters were disrupted at EAN-PM nodes. Neurofascin and gliomedin, two cell adhesion molecules involved with aggregating Nav channels at nodes, were selectively affected prior to demyelination in EAN-PM, indicating that degradation of the axo-glial unit initiated node alteration. This was associated with autoantibodies to neurofascin and gliomedin. Node disruption was, however, independent from complement deposition at nodes, and deposits of the terminal complement complex (C5b-9) were found on the external surface of Schwann cells in EAN-PM. In these animals, the paranodal junctions were also affected and Kv1 channels, which are normally juxtaparanodal, were found dispersed at nodes and paranodes. Altogether, these alterations were associated with conduction deficits in EAN-PM ventral spinal roots. EAN-P2 animals also exhibited inflammatory demyelination, but did not show alteration in nodal clusters or autoantibodies. Our results highlighted the complex mechanisms underlying conduction abnormalities in demyelinating disorders, and unraveled neurofascin and gliomedin as two novel immune targets in experimental allergic neuritis.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/fisiología , Moléculas de Adhesión Celular/fisiología , Síndrome de Guillain-Barré/metabolismo , Factores de Crecimiento Nervioso/fisiología , Neuritis Autoinmune Experimental/metabolismo , Nódulos de Ranvier/metabolismo , Animales , Autoanticuerpos/inmunología , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular Neuronal/inmunología , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Modelos Animales de Enfermedad , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/patología , Masculino , Factores de Crecimiento Nervioso/inmunología , Conducción Nerviosa , Neuritis Autoinmune Experimental/inmunología , Neuritis Autoinmune Experimental/patología , Canales de Potasio con Entrada de Voltaje , Ratas , Ratas Endogámicas Lew , Células de Schwann/inmunología , Canales de Sodio/fisiología , Raíces Nerviosas Espinales/fisiopatologíaRESUMEN
Voltage-gated Na(+) channels (Nav) are the targets of a variety of scorpion toxins. Here, we investigated the effects of Amm VIII, a toxin isolated from the venom of the scorpion Androctonus mauretanicus mauretanicus, on pain-related behaviours in mice. The effects of Amm VIII were compared with the classic scorpion α-toxin AaH II from Androctonus australis. Contrary to AaH II, intraplantar injection of Amm VIII at relatively high concentrations caused little nocifensive behaviours. However, Amm VIII induced rapid mechanical and thermal pain hypersensitivities. We evaluated the toxins' effects on Nav currents in nociceptive dorsal root ganglion (DRG) neurons and immortalized DRG neuron-derived F11 cells. Amm VIII and AaH II enhanced tetrodotoxin-sensitive (TTX-S) Nav currents in DRG and F11 cells. Both toxins impaired fast inactivation and negatively shifted activation. AaH II was more potent than Amm VIII at modulating TTX-S Nav currents with EC50 of 5 nM and 1 µM, respectively. AaH II and Amm VIII also impaired fast inactivation of Nav1.7, with EC50 of 6.8 nM and 1.76 µM, respectively. Neither Nav1.8 nor Nav1.9 was affected by the toxins. AaH II and Amm VIII reduced first spike latency and lowered action potential threshold. Amm VIII was less efficient than AaH II in increasing the gain of the firing frequency-stimulation relationship. In conclusion, our data show that Amm VIII, although less potent than AaH II, acts as a gating-modifier peptide reminiscent of classic α-toxins, and suggest that its hyperalgesic effects can be ascribed to gain-of-function of TTX-S Na(+) channels in nociceptors.
Asunto(s)
Hipersensibilidad/etiología , Dolor/inducido químicamente , Venenos de Escorpión/toxicidad , Canales de Sodio/metabolismo , Animales , Fenómenos Biofísicos/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ganglios Espinales/citología , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hipersensibilidad/tratamiento farmacológico , Masculino , Potenciales de la Membrana/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Umbral del Dolor/efectos de los fármacos , Ratas , Venenos de Escorpión/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/efectos de los fármacos , Tetrodotoxina/farmacología , Tetrodotoxina/uso terapéuticoRESUMEN
Cutaneous mechanoreceptors are localized in the various layers of the skin where they detect a wide range of mechanical stimuli, including light brush, stretch, vibration and noxious pressure. This variety of stimuli is matched by a diverse array of specialized mechanoreceptors that respond to cutaneous deformation in a specific way and relay these stimuli to higher brain structures. Studies across mechanoreceptors and genetically tractable sensory nerve endings are beginning to uncover touch sensation mechanisms. Work in this field has provided researchers with a more thorough understanding of the circuit organization underlying the perception of touch. Novel ion channels have emerged as candidates for transduction molecules and properties of mechanically gated currents improved our understanding of the mechanisms of adaptation to tactile stimuli. This review highlights the progress made in characterizing functional properties of mechanoreceptors in hairy and glabrous skin and ion channels that detect mechanical inputs and shape mechanoreceptor adaptation.
Asunto(s)
Mecanorreceptores/metabolismo , Tacto/fisiología , Animales , Humanos , Canales Iónicos/metabolismo , Mecanorreceptores/química , Neuronas/fisiología , Piel/metabolismo , Médula Espinal/metabolismoRESUMEN
Luminal B breast cancers represent a fraction of oestrogen receptor (ER)-positive tumours associated with poor recurrence-free and disease-specific survival in all adjuvant systemic treatment categories including hormone therapy alone. Identification of specific signalling pathways driving luminal B biology is paramount to improve treatment. We have studied 100 luminal breast tumours by combined analysis of genome copy number aberrations and gene expression. We show that amplification of the ZNF703 gene, located in chromosomal region 8p12, preferentially occurs in luminal B tumours. We explored the functional role of ZNF703 in luminal B tumours by overexpressing ZNF703 in the MCF7 luminal cell line. Using mass spectrometry, we identified ZNF703 as a co-factor of a nuclear complex comprising DCAF7, PHB2 and NCOR2. ZNF703 expression results in the activation of stem cell-related gene expression leading to an increase in cancer stem cells. Moreover, we show that ZNF703 is implicated in the regulation of ER and E2F1 transcription factor. These findings point out the prominent role of ZNF703 in transcription modulation, stem cell regulation and luminal B oncogenesis.