RESUMEN
A complex of stomatin-family proteins and acid-sensing (proton-gated) ion channel (ASIC) family members participate in sensory transduction in invertebrates and vertebrates. Here, we have examined the role of the stomatin-family protein stomatin-like protein-3 (STOML3) in this process. We demonstrate that STOML3 interacts with stomatin and ASIC subunits and that this occurs in a highly mobile vesicle pool in dorsal root ganglia (DRG) neurons and Chinese hamster ovary cells. We identify a hydrophobic region in the N-terminus of STOML3 that is required for vesicular localization of STOML3 and regulates physical and functional interaction with ASICs. We further characterize STOML3-containing vesicles in DRG neurons and show that they are Rab11-positive, but not part of the early-endosomal, lysosomal or Rab14-dependent biosynthetic compartment. Moreover, uncoupling of vesicles from microtubules leads to incorporation of STOML3 into the plasma membrane and increased acid-gated currents. Thus, STOML3 defines a vesicle pool in which it associates with molecules that have critical roles in sensory transduction. We suggest that the molecular features of this vesicular pool may be characteristic of a 'transducosome' in sensory neurons.
Asunto(s)
Canales Iónicos Sensibles al Ácido/metabolismo , Proteínas Sanguíneas/metabolismo , Ganglios Espinales/metabolismo , Proteínas de la Membrana/metabolismo , Complejos Multiproteicos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Células Receptoras Sensoriales/metabolismo , Vesículas Transportadoras/metabolismo , Canales Iónicos Sensibles al Ácido/genética , Animales , Proteínas Sanguíneas/genética , Células CHO , Cricetinae , Cricetulus , Ganglios Espinales/citología , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Complejos Multiproteicos/genética , Proteínas del Tejido Nervioso/genética , Estructura Terciaria de Proteína , Células Receptoras Sensoriales/citología , Vesículas Transportadoras/genética , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismoRESUMEN
Chronic high-frequency stimulation (HFS) of the subthalamic nucleus (STN) protects nigral dopaminergic neurons from neurodegeneration in animal models of Parkinson's disease (PD). However, these data are challenged by the lack of control for neuroprotective effects that might be related to tissue damage due to electrode insertion or STN-HFS. Here we report the first placebo-controlled study on continuous STN-HFS in a rat model of PD using an implantable microstimulation system. We found a significant increase of preserved dopaminergic nigral neurons on the lesioned side (expressed as ratio to the non-lesioned side) of approximately 50% in comparison to STN sham-stimulated and STN-naive rats. These data provide evidence for the phenotypic rescue of nigral dopamine neurons by long-term STN-HFS in this animal model of PD.
Asunto(s)
Dopamina/metabolismo , Estimulación Eléctrica/métodos , Neuronas/patología , Enfermedad de Parkinson/terapia , Sustancia Negra/patología , Núcleo Subtalámico/efectos de la radiación , Animales , Modelos Animales de Enfermedad , Masculino , Enfermedad de Parkinson/patología , Ratas , Ratas Wistar , Núcleo Subtalámico/fisiologíaRESUMEN
TRPA1 is an ion channel expressed by nociceptors and activated by irritant compounds such as mustard oil. The endogenous function of TRPA1 has remained unclear, a fact highlighted by ongoing debate over its potential role as a sensor of noxious cold. Here we show that intracellular Ca(2+) activates human TRPA1 via an EF-hand domain and that cold sensitivity occurs indirectly (and nonphysiologically) through increased [Ca(2+)](i) during cooling in heterologous systems.